The ubiquitin-proteasome system and learning-dependent synaptic plasticity - a 10 year update

Morgan B Patrick; Nour Omar; Craig T Werner; Swarup Mitra; Timothy J Jarome

doi:10.1016/j.neubiorev.2023.105280

. Author manuscript; available in PMC: 2024 Sep 1.

Published in final edited form as: Neurosci Biobehav Rev. 2023 Jun 12;152:105280. doi: 10.1016/j.neubiorev.2023.105280

The ubiquitin-proteasome system and learning-dependent synaptic plasticity - a 10 year update

Morgan B Patrick ^1,^*, Nour Omar ^1,^*, Craig T Werner ^2,^3,^{^}, Swarup Mitra ^4,^{^}, Timothy J Jarome ^1,^5,^{^}

PMCID: PMC11323321 NIHMSID: NIHMS1910407 PMID: 37315660

Abstract

Over 25 years ago, a seminal paper demonstrated that the ubiquitin-proteasome system (UPS) was involved in activity-dependent synaptic plasticity. Interest in this topic began to expand around 2008 following another seminal paper showing that UPS-mediated protein degradation controlled the “destabilization” of memories following retrieval, though we remained with only a basic understanding of how the UPS regulated activity- and learning-dependent synaptic plasticity. However, over the last 10 years there has been an explosion of papers on this topic that has significantly changed our understanding of how ubiquitin-proteasome signaling regulates synaptic plasticity and memory formation. Importantly, we now know that the UPS controls much more than protein degradation, is involved in plasticity underlying drugs of abuse and that there are significant sex differences in how ubiquitin-proteasome signaling is used for memory storage processes. Here, we aim to provide a critical 10-year update on the role of ubiquitin-proteasome signaling in synaptic plasticity and memory formation, including updated cellular models of how ubiquitin-proteasome activity could be regulating learning-dependent synaptic plasticity in the brain.

Keywords: Ubiquitin, Proteasome, Memory, Substance Use Disorder, Sex Differences

1. Introduction

The process of memory storage is dynamic, requiring the coordinated actions of numerous intracellular molecules and signaling cascades to regulate increased transcriptional regulation and de novo protein synthesis (Asok et al., 2019; Johansen et al., 2011). Once acquired, memories can proceed through several stages that include their initial storage, or consolidation, and their subsequent modification or updating following retrieval, known as reconsolidation (McGaugh, 2015). This latter reconsolidation stage has been shown to allow incorporation of new information into or the strengthening or weakening of the original memory (Alberini, 2011). Thus, memories are dynamic and are not necessarily static following their initial formation.

Over the last thirty years a plethora of studies have tried elucidating the molecular mechanisms that support memory storage processes. From these studies it has become clear that 1) memory storage, at any stage, has a general need for increased transcriptional control and new protein synthesis (Bailey et al., 1999; Nader et al., 2000; Schafe et al., 1999), 2) memories are stored across a distributed network of brain regions that varies based on the type/modality of the task that is learned (Helmstetter et al., 2008), and 3) the stages of memory storage, such as consolidation and reconsolidation, share some, but not all, the same molecular mechanisms (Alberini, 2005; Mamiya et al., 2009; Orsi et al., 2019; Suzuki et al., 2004). For example, one of the most widely used behavioral paradigms, contextual fear conditioning, requires the hippocampus, amygdala, and prefrontal cortex and retrosplenial cortex (Bailey et al., 1999; Kim and Fanselow, 1992; Vann et al., 2009), among other regions, for long-term memory formation. Conversely, auditory fear memories require the amygdala, but not the hippocampus, while nonaversive spatial memories, such as the Morris water maze and objection location testing, require the hippocampus but not amygdala. Thus, the most studied regions, the hippocampus and amygdala, have specific roles in processing contextual and spatial information or the emotional valence of the task, respectively.

In addition to changes in gene transcription and protein translation in these brain regions, more recently, studies have begun to focus on the idea that changes in gene transcription and protein translation are accompanied by increased protein degradation (Hegde, 2017; Jarome and Helmstetter, 2013, 2014). In fact, to date, strong evidence now supports a role for protein degradation in the memory consolidation and reconsolidation processes (Figueiredo et al., 2015; Jarome et al., 2011; Lee et al., 2008; Lopez-Salon et al., 2001; Massaly et al., 2013; Reis et al., 2013; Rodriguez-Ortiz et al., 2011; Rosenberg et al., 2016a; Werner et al., 2015), which has changed our understanding of how memories are stored and modified in the brain. The majority of protein degradation in cells occurs via the ubiquitin-proteasome system (UPS), which is highly conserved across all prokaryotic and eukaryotic organisms (Hershko and Ciechanover, 1998). Ten years ago, we published a review summarizing the rapidly expanding evidence supporting a role for ubiquitin-proteasome mediated protein degradation in activity- and learning-dependent synaptic plasticity in the brain (Jarome and Helmstetter, 2013). In this prior review, we proposed a framework by which ubiquitin-proteasome activity could be regulating synaptic plasticity and memory consolidation and reconsolidation in cells. However, due to evidence presented in the decade that has followed, it has become clear that these initial models were incorrect for a number of reasons. Most notable is that they did not account for degradation-independent functions of the ubiquitin-proteasome system. Instead their work focused on candidate-driven target identification methods that may have introduced bias and that males and females could differ in how they use this system to store the same memories during consolidation and reconsolidation. Thus, the use of only males in prior work suggest that our brains operate in an identical manner in males and females, targeting the same proteins for degradation following learning when in fact this was never tested. Here, we seek to provide a renewed understanding of this mechanism by providing thorough update on this rapidly emerging topic, emphasizing those new data that have been published over the last 10 years. Further, we integrate these new data with that which was previously published and conclude by proposing key areas that have yet to be addressed on this topic.

2. Ubiquitin-Proteasome System

As mentioned above, the majority of protein degradation (greater than 90%) occurs via the UPS. The highly complex system consists of two independent parts, the 26S proteasome, which degrades proteins, and the small protein modifier called ubiquitin, which marks proteins for degradation or other non-proteolytic functions. Despite the complexity of the large proteasome structure (reviewed below), ubiquitin, a small 76 amino acid protein that sole purpose is to bind other proteins, may perhaps have an even more diverse functions in the cell. In this section, we provide a brief overview on the structure of the proteasome and the coordination and diversity of the ubiquitination process. We also refer readers to more detailed discussions on these topics.

2.1. Proteasome Structure

In eukaryotic cells, the ubiquitin-proteasome system is responsible for the degradation of misfolded proteins to maintain intracellular homeostasis. The proteasome is a large protein complex in cells containing proteases and functions to degrade unneeded or damaged proteins that the small protein modifier ubiquitin has tagged (Figure 1). The typical proteasome is composed of ~33 different subunits with a molecular weight of 2.5MDa (Bard et al., 2018; Bedford et al., 2010). There is an argument on the structural division of this large 26S proteasome particle complex containing three different proteolytic sites, which allows the opportunity for this particle to degrade a multitude of amino acid sequences. However, the proteasome core has been agreed upon as having a cylindrical 20S catalytic core particle composed of four heptameric rings stacked together on top of each other with 19S regulatory particles linked on each end that serves to regulate the activity of the 20S core, though some 20S cores can contain only a single or, in some cases, no 19S cap. The two inner rings of the 20S core consist of seven beta subunits, with β1, β2, and β5 regulating the three types of proteasome catalytic activity: chymotrypsin-, trypsin- and peptidylglutamyl peptide hydrolyzing-like activity. These seven beta subunits face the lumen of the barrel. In comparison, the seven related alpha subunits flank the beta subunits, forming a gate that prevents unwanted proteins from penetrating the barrel of the complex.

Figure 1. — The small ubiquitin protein is attached to a target substrate through a series of ATP-dependent processes requiring the ubiquitin activation enzyme (E1) and numerous ubiquitin conjugation enzymes (E2) and ubiquitin ligases (E3). The target substrate can acquire a single (monoubiquitination) or multiple (2–7; polyubiquitination) ubiquitin molecules. While monoubiquitination is generally independent of the protein degradation process, many, but not all, polyubiquitinated proteins are marked for destruction by the 26S proteasome complex.

Ubiquitinated substrates initially bind to the 19S regulatory particle so they can be deubiquitinated before translocation to the 20S catalytic core. The 19S regulatory protein is divided into two parts: the lid and the base. The base is closer to the 20S catalytic core, which supports the 19S protein’s role in the final regulatory steps towards the 20S catalytic core. This base is made of two leucine-rich proteins, RPN1 (S2), RPN2 (S1), various deubiquitinating enzymes, and six ATPase proteins (RPT1–6). According to archaeal analogs, the six RPT proteins are linked to the alpha ring to gate the channels and translocate the substrates. Importantly, these RPT proteins regulate the function of the 20S core via an ATP-dependent process. Most notable is the RPT6 protein, which has been extensively studied due to numerous reports demonstrating that phosphorylation at Serine-120 (pRPT-S120) can control the activity of the 20S core and regulate synaptic plasticity, dendritic spine growth and perhaps memory formation (Djakovic et al., 2012; Djakovic et al., 2009; Gonzales et al., 2018; Hamilton et al., 2012; Jarome et al., 2013; Marquez-Lona et al., 2017; Scudder et al., 2021). This potentially unique function of RPT6 will be discussed in more detail in later sections.

2.2. Ubiquitination Process

The proteasome and the polymerization of ubiquitin signal work in unison to trigger the degradation of target proteins. Similar to the proteasome, the ubiquitination process is highly complex (Figure 2). There are four genes within the human genome that code for ubiquitin, UBB, UBC, UBA52, and RPS27A, though, interestingly, there are also over 52 pseudogenes of these genes. UBB and UBC redundantly code poly-ubiquitin precursors, while a single copy of ubiquitin fused into the ribosomal proteins L40 and S27A are coded by UBA52 and RPS27A, respectively. All four genes contribute to the free ubiquitin pool, or the amount of unconjugated (free) ubiquitin available at any given time that can be attached to target substrates, though further studies are needed about the individual contributions of each gene to the ubiquitin pool (Hallengren et al., 2013; Park and Ryu, 2014). Target proteins can acquire 1–7 ubiquitin modifications, though to begin the destruction of the target, there usually needs to be four or more ubiquitin molecules covalently attached (Akutsu et al., 2016; Musaus et al., 2020). Three classes of enzymes regulate the ubiquitination process: E1 (ubiquitin-activating), E2 (ubiquitin-conjugating), and E3 (ubiquitin-ligases) enzymes. The first step begins with the E1 enzyme. Numerous enzymes from E1, E2, and E3 are mobilized for accurate selection of the proteins. However, E1, E2, and E3 protein concentrations differ. This differentiation allows for high selectivity and the ability to recognize a specific protein substrate for ubiquitylation. Furthermore, if there is a mistake, this initial ubiquitination process is a reversible reaction.

Figure 2. — A complete 26S proteasome complex consists of a 20S catalytic core surrounded by two 19S regulatory caps. The core consists of two outer rings of alpha subunits surrounding two inner rings of beta subunits, the latter of which possess the catalytic function of the entire 26S complex. The 19S caps contain a variety of deubiquitination and other ATP-independent regulatory subunits, called RPNs, and the only six ATPase subunits of the proteasome, called RPTs.

As noted above, proteins can acquire 1–7 ubiquitin modifications, which leads to unique cellular fates (Akutsu et al., 2016; Musaus et al., 2020). Monoubiquitination, conjugating a single ubiquitin to a target protein, usually targets substrates for fates independent of protein degradation. Notable is that proteins can acquire multiple ubiquitin modifications that are not linked, known as multi monoubiquitination, or the single ubiquitin modification can be further extended by additional ubiquitin molecules linked directly to it to form elongated chains, also known as polyubiquitination. There are several types of polyubiquitin linkage sites: Methionine 1 (M1) and Lysines (K) 6, 11, 27, 29, 33, 48 and 63, though the literature has been focused on the two most abundant, K48- and K63 polyubiquitination. K48-linked polyubiquitination is the canonical signal for degradation as it interacts with the proteasome with a high affinity. Conversely, K63-linked polyubiquitination approaches a destructive fate for the target through autophagy rather than the proteasome and is also involved in a wide variety of potential functions that are independent of protein degradation, such as endocytosis and the DNA damage response. In fact, several of these polyubiquitin modifications are independent of the protein degradation process, including the only atypical mark M1, also known as linear polyubiquitination. Regardless of the mark acquired, the ubiquitination process is reversible by deubiquitinating enzymes, which can partially or completely strip all ubiquitin molecules from the protein.

3. The ubiquitin-proteasome system and activity-dependent synaptic plasticity

Numerous studies have shown that there is a role of protein degradation in activity-dependent synaptic plasticity (Hegde, 2017; Hegde et al., 2014). As these have been discussed in detail previously (Jarome and Helmstetter, 2013), we only briefly summarize some of the major findings here. In 2003, Ehlers discovered that dynamic changes in the protein composition of the postsynaptic density (PSD) occur following chronic inhibition or stimulation of hippocampal neurons (Ehlers, 2003). Importantly, he determined that many of these changes are largely due to the proteasome-dependent degradation of proteins in the PSD. Following this, evidence emerged that synaptic stimulation caused a redistribution of the proteasome from the dendritic shift to the spine, where the redistributed proteasomes would subsequently become more active (Bingol and Schuman, 2006). Calcium/calmodulin dependent protein kinase II (CaMKII) regulates a majority of this redistribution of proteasomes following synaptic excitation and also acts as a scaffold to recruit proteasomes to dendritic spines (Bingol et al., 2010). The phosphorylation of RPT6-S120 happens by CaMKII once at the spines, which leads to an increase in proteasome activity. Consistent with this, CaMKII has been shown to target RPT6-S120 in vitro and transfecting cultured hippocampal cells with a phospho-dead mutant for RPT6-S120 reduced the activity-dependent accumulation of proteasomes to the PSD, while RPT6-S120 phosphorylation mimicked changes in synaptic strength that would typically result from chronic stimulation or inhibition of neurons (Djakovic et al., 2012; Djakovic et al., 2009). Supporting this, pRPT6-S120 is required for activity-dependent growth of new dendritic spines (Hamilton et al., 2012).

Long-term depression (LTD) and long-term potentiation (LTP) have also been shown to have an important dependency on protein degradation, although there is conflicting evidence. There have been several studies that show enhancement or inhibition of early LTP (E-LTP) from proteasome inhibition, with the enhancement being protein synthesis independent and likely due to the stabilization of pre-existing proteins (Dong et al., 2014; Dong et al., 2008). Additionally, an enhancement of the early part of the L-LTP (Ep-L-LTP) was observed following proteasome inhibition, which depended on translation of pre-existing mRNA. In contrast, other studies report no effect due to administration of proteasome inhibitors (Fonseca et al., 2006), though this discrepant finding may be due to differences in the proteasome inhibitor and concentration used. However, late LTP (L-LTP) has been consistently shown to be impaired as a result of proteasome inhibition, suggesting that L-LTP requires protein degradation in addition to the well-described need for gene transcription and protein synthesis. Interestingly, Fonseca and colleagues demonstrated that during L-LTP if protein degradation and protein synthesis are simultaneously inhibited, this results in a rescue of LTP which under normal conditions would be lost due to blocking only one of these mechanisms independently (Fonseca et al., 2006). Henceforth, a balance between protein degradation and protein synthesis is critical for L-LTP. Moreover, there is conflicting evidence as to whether impairment of both metabotropic glutamate receptor-dependent and NMDA receptor (NMDAR)-dependent LTD is caused by inhibiting proteasome activity (Klein et al., 2015; Li et al., 2016). Despite these conflicting results, it remains clear that protein degradation is crucial for L-LTP despite the lack of clarity on the circumstances in which it is necessary for LTD and E-LTP.

While new data has not emerged on this topic in the last 10 years, long-term facilitation (LTF) experiments in Aplysia were fundamental to advancing knowledge of protein degradation in learning-dependent synaptic plasticity. Work from Hegde and colleagues was the first to show a potential role of proteasome-dependent protein degradation in synaptic plasticity (Hegde et al., 1993). Further, subsequent work from this group showed a critical role for a majority deubiquitinating enzyme in LTF (Hegde et al., 1997). This was then followed by the first evidence that proteasome inhibitors could prevent LTF induction (Chain et al., 1999). Ultimately, these studies set the basis for the next 20 years of work on the important of ubiquitin-proteasome signaling to activity- and learning-dependent synaptic plasticity.

4. Protein Degradation and Memory: The importance of sex as a biological variable

Numerous studies have supported a role for the degradation function of the ubiquitin-proteasome system in learning-dependent synaptic plasticity. While the initial work focused on only males, over the last few years evidence has emerged that males and females differ in how they regulate, engage, and use protein degradation in the brain during storage of the same memories. In this section, we discuss the evidence supporting a role for proteasome-mediated protein degradation in the memory consolidation and reconsolidation processes, emphasizing how this varies between sexes.

4.1. Memory Consolidation

4.1.1. Inhibition of protein degradation

Similar to synaptic plasticity, numerous studies have supported a role for the protein degradation function of the UPS in the memory consolidation process. A majority of the evidence, to date, supports a role for protein degradation in memory consolidation in the amygdala and hippocampus, though a few other brain regions have been implicated as well. Some of the earliest reports found that when the proteasome inhibitor β-lac is injected into the rodent amygdala around the time of training this resulted in male rodents having memory impairments for contextual and auditory fear conditioning (Jarome et al., 2011). More recently, we found similar impairments in female rats following genetic inhibition of the proteasome via CRISPR-dCas9-mediated transcriptional silencing of major proteasome subunits in the amygdala (Devulapalli et al., 2021). Supporting this sex-independent need for protein degradation in the amygdala, genetic upregulation of proteasome function via CRISPR-dCas9-mediated transcriptional activation of major proteasome subunits in the amygdala enhances contextual fear in both male and female rats. Conversely, in the hippocampus pharmacological inhibition of the proteasome does not impair contextual fear memory in male animals (Lee et al., 2008). Consistent with this, genetic inhibition of proteasome function in the hippocampus selectively impairs contextual fear memory in female, but not male, rats (Martin et al., 2021). Together, these data suggest that sex differences exist in the need for protein degradation across brain regions during fear memory formation.

Despite this reported sex effect most of the literature has focused on male animals, leaving a number of unanswered questions about whether a similar requirement for protein degradation occurs in specific brain regions in females during the consolidation of memory for certain behavioral tasks. For example, when UPS proteasome function was inhibited in the prefrontal cortex (PFC) of trace fear conditioned male rodents, memory consolidation was impaired (Reis et al., 2013). This supports the role of proteasomal degradation in trace fear memory consolidation in the PFC. However, no further studies, to date, have been done to determine the role of protein degradation in the female PFC during trace fear conditioning. Similarly, when the proteasome inhibitor lactacystin, a precursor to β-lac, was injected into the hippocampal region, male animals had impaired memory for the Morris water maze and inhibitory avoidance tasks (Artinian et al., 2008; Lopez-Salon et al., 2001), though again this has not been tested in females. Interestingly, proteasome inhibition in the insular cortex, but not the amygdala, prevented long-term memory consolidation for a conditioned taste aversion task in male rodents (Rodriguez-Ortiz et al., 2011). Further, the relationship between object recognition and protein degradation was recently tested and no effect was found following proteasome inhibition in the hippocampus of male rodents (Furini et al., 2015). It is important to note that all these studies were conducted on male rodents and have not been replicated in females, with the exception that sex differences in ubiquitinproteasome activation have been reported in the hippocampus and PFC following object training (Beamish et al., 2022). Since sex differences seem to be prominent in the regulation and use of protein degradation in the brain, this leaves a significant gap in the field that needs to be addressed in future studies.

4.1.2. Regulation of protein degradation

Several studies have also examined how the protein degradation process is regulated during memory formation with most of this work being done in male rodents. The first evidence suggested that ubiquitin-proteasome mediated protein degradation is NMDAR-dependent as learning-related increases in protein ubiquitination were lost following blockade of NMDARs (Jarome et al., 2011). Further evidence suggests that CaMKII is potentially downstream of this increase in calcium signaling and is responsible for increases in proteasomes activity in the amygdala following fear conditioning (Jarome et al., 2013). Interestingly, it was found that CaMKII, but not PKA, inhibition in the amygdala also prevented learning-related increases in RPT6-S120 phosphorylation. This data suggests that CaMKII could be regulating memory formation in the amygdala via RPT6 phosphorylation, though this has never been directly tested. This will be discussed more in a later section. Further studies have shown regulation of the protein degradation process by NMDARs and muscarinic acetylcholine receptors (mAChr) in the gustatory cortex (Rosenberg et al., 2016a; Rosenberg et al., 2016b), the prior further supporting a link between calcium signaling and ubiquitin-proteasome function during memory formation.

More recent evidence has expanded on the conditions under which CaMKII and PKA can regulate proteasome function during memory consolidation. Notable, it was found that contrary to our prior report, both CaMKII and PKA can regulate proteasome function in the amygdala and hippocampus following contextual fear conditioning (Devulapalli et al., 2019). However, the conditions that each did so varied based upon the subcellular compartments (nucleus, cytoplasm or synaptic region), the brain region, and the type of proteasome activity being assessed. Importantly, the ability of CaMKII and PKA to both regulate proteasome function was shared across sexes, though the conditions under which each did varied between males and females. Regardless, this is the first data demonstrating that ubiquitin-proteasome activity could be regulated by similar mechanisms in the male and female brain, though more studies are needed in this area.

4.1.3. Temporal dynamics of protein degradation following learning

In addition to regulatory processes, several studies have examined the temporal dynamics of the protein degradation process. Some of the earliest evidence indicated that proteasomal-targeting of proteins for degradation increased in the hippocampus 4 hours after behavioral training (Lopez-Salon et al., 2001). Consistent with this, degradation-specific protein polyubiquitination levels have been shown to rapidly increase in the amygdala 30 minutes following fear conditioning, where they remain elevated for at least 4 hours before returning to baseline by 6 hours post-training in male rodents (Jarome et al., 2013; Jarome et al., 2011). This increase in protein degradation occurs in a similar timeline as translational control mechanisms, suggesting overlap between these two processes. Accordingly, most studies, to date, have focused on the 1 and 4 hour time points post-training for examining changes in the protein degradation process, especially the former, which has shown consistency across the prefrontal cortex, amygdala, hippocampus and gustatory cortex (Jarome et al., 2011; Martin et al., 2021; Orsi et al., 2019; Reis et al., 2013; Rosenberg et al., 2016a; Rosenberg et al., 2016b). As a result, it is clear that protein degradation is rapidly engaged in select brain regions following learning. However, it is important to note that there may be sex differences in the temporal dynamics of the protein degradation process, though this evidence remains limited due to the seldom use of female animals in the published literature, to date. Importantly, we found that protein degradation is increased at 1 hour after contextual fear conditioning in the female amygdala and hippocampus, the latter of which was not seen in male rats (Farrell et al., 2021; Martin et al., 2021). As a result, there may be sex differences in the temporal dynamics of the protein degradation process across brain regions during memory consolidation, though this needs explored in more detail due to the general lack of use of female rodents in prior work.

4.1.4. Subcellular localization of protein degradation following learning

The ubiquitin-proteasome machinery is located in every subcellular compartment, though appears to be most abundant in the cytoplasm and nucleus. However, only recently have studies begun examining how protein degradation is altered in specific subcellular compartments as a result of learning. For example, in the amygdala of male, but not female, rats, global increases in degradation-specific K48 polyubiquitination and proteasome activity are observed within 1 hour of contextual fear conditioning (Jarome et al., 2011; Orsi et al., 2019). Conversely, in the hippocampus of female, but not male, rats, global increases in proteasome activity are observed 1 hour after contextual fear conditioning (Martin et al., 2021). Important here is that in both sexes protein degradation appears to be largely confined to the nucleus during the early consolidation process. However, this was based on broader analyses of protein degradation. More recent evidence from our group using highly sensitive proteomic analyses that can determine changes in K48 polyubiquitin targeting of individual proteins have revealed that protein degradation is not confined to a single subcellular compartment during the early consolidation process as proteins are widely targeted throughout the cell, including in the nucleus, cytoplasm and even synaptic region (Farrell et al., 2021).

4.1.5. Protein targets of protein degradation during memory consolidation

While strong evidence exists for proteasome-mediated protein degradation being involved in memory consolidation, few studies have tried to identify the protein targets of ubiquitin following learning. Early studies used candidate-driven approaches to identify protein targets of the proteasome, with most the emphasis being those that had been identified in seminal in vitro studies. For example, in both the amygdala and hippocampus of male rodents, fear conditioning increases the targeting of the synaptic scaffolding protein SHANK for degradation (Jarome et al., 2011; Lee et al., 2008). Furthermore, the RNAi-induced Silencing Complex (RISC) factor MOV10 and the transcriptional repressor IkB protein have been shown to be targets of the proteasome in the amygdala and hippocampus, respectively, of male rodents following behavioral training (Jarome et al., 2011; Lopez-Salon et al., 2001). Together, these early studies suggested that protein degradation could be involved in control of transcriptional and translational processes and synaptic remodeling following learning, which formed the basis for our original proposed models on ubiquitin-proteasome signaling in memory consolidation (Jarome and Helmstetter, 2013).

While useful, these candidate-driven approaches provided limited information on the protein targets of the proteasome following learning and suffered from concerns over specificity of the antibodies used in such analyses. Furthermore, they had only been completed in male rodents without consideration for whether similar proteins were targeted in females. To address these concerns, using a tandem ubiquitin binding entity (TUBE) in combination with liquid chromatography mass spectrometry, we recently completed the first proteomic analysis of K48 polyubiquitinated proteins in the amygdala of male and female rats following contextual fear conditioning (Farrell et al., 2021). In total, over 110 proteins were identified as targets of K48 polyubiquitin-mediated proteasomal degradation within 1 hour of fear conditioning. Interestingly, females had more than twice as many K48 polyubiquitin targets as males, suggesting a more robust degradation process in the female amygdala, and only 3 proteins were identified as a target in both sexes all of which were exclusively found in astrocytes. This surprising result indicates that males and females largely target different proteins with K48 polyubiquitination following learning, suggesting sex-specific functional roles for protein degradation during memory consolidation. Consistent with this, the functional protein pathways were largely different between sexes. In terms of the target proteins, in females vesicular transport through interactions with t-SNAREs 1B (VTI1B), a vesicular transport pathway critical for synaptogenesis, had the largest fold change in K48 polyubiquitin targeting as a result of fear conditioning. Conversely, one of the only proteins to be targeted in both sexes was GFAP, a critical component of astrocyte structure, suggesting that protein degradation may be occurring in astrocytes in both sexes following learning. Notable here is that using a cell-type specific CRISPR-dCas9 approach, we recently found that both neuronal and astrocytic protein degradation was critical for contextual fear memory consolidation in the amygdala (Farrell et al., 2023a), supporting that both neuronal and non-neuronal cell types require protein degradation for memory formation. These data fit with an emerging literature demonstrating that similar to neurons, astrocytes have a critical role in memory formation where they can modulate communication between brain regions and cell types (Adamsky and Goshen, 2018; Adamsky et al., 2018; Fan et al., 2021; Kol et al., 2020; Suzuki et al., 2011). Considering that GFAP, a critical component of the astrocyte structure, was being targeted by the proteasome following learning, it is possible then that protein degradation could be involved in altering the astrocyte structure to increase cell-to-cell communication, though this has not been directly tested. Regardless, this unbiased proteomic approach has changed our understanding of how protein degradation is likely contributing to the memory consolidation process, challenging ideas that were originally proposed in previous models.

4.2. Memory Reconsolidation

4.2.1. Inhibition of protein degradation

When a memory is retrieved, or reactivated, it is rendered susceptible to distribution via a process known as reconsolidation, which is thought to be involved in updating the memory. While less studied than consolidation, strong evidence supports a role for protein degradation in the memory reconsolidation process. A seminal study by Lee and colleagues found that degradation-specific protein polyubiquitination was rapidly increased in the hippocampus of male mice following contextual fear conditioning (Lee et al., 2008). Further, while injection of a proteasome inhibitor into the CA1 region of the dorsal hippocampus did not impair memory, it rescued the memory deficits that normally resulted from protein synthesis blockade. This was the first evidence to suggest that ubiquitin-proteasome mediated protein degradation controlled the destabilization of the memory, leading to the need for new protein synthesis in order for the memory to be reconsolidated. These data were supported by similar results in the amygdala (Jarome et al., 2011), as well as from other studies showing that retrieval-dependent memory updating is related to changes in and could be prevented by blocking functional proteasome activity (Jarome et al., 2015; Lee, 2008). This has led to the widely accepted theory that protein degradation regulates the destabilization of memories following retrieval. However, it should be noted that some studies have reported impairments in memory following post-retrieval inhibition of proteasome function (Artinian et al., 2008). Furthermore, all of the studies on ubiquitin-proteasome signaling in reconsolidation, to date, have been done with only male rodents, leaving a number of questions about whether protein degradation also regulates the destabilization of memory in females.

4.2.2. Regulation of protein degradation

Research on regulation of protein degradation during memory reconsolidation has been limited. However, limited evidence suggests that NMDARs and CaMKII-dependent regulation of pRPT6-S120 levels has a pivotal role in controlling proteasome function during the post-retrieval period (Jarome et al., 2016; Jarome et al., 2011). In the latter study, they demonstrated that in male rodents pRPT6-S120 levels and proteasome activity were enhanced in the amygdala following the retrieval of a contextual fear memory. Pharmacological manipulation of CaMKII in the amygdala prevented retrieval-dependent increases in proteasome activity and RPT6-S120 phosphorylation. Importantly, inhibition of CaMKII by itself did not impair memory retrieval, but did rescue the impairments that normally resulted from protein synthesis blockade. In summary, CaMKII regulates protein degradation during memory reconsolidation, which may occur via control over phosphorylation of RPT6-S120.

4.2.3. Temporal dynamics of protein degradation following retrieval

Despite the well-established role of protein degradation in memory reconsolidation, only a few studies have examined the temporal dynamics of this process. Much of these findings come from only two labs, both using contextual fear conditioning models in male rodents. Lee and colleagues found that degradation-specific protein polyubiquitination increased in the mouse hippocampus soon after retrieval and was resolved (returned to baseline) by 6 hours (Lee et al., 2008). Similar results were found by our group, though in this case post-retrieval increases in protein degradation in the male amygdala returned to baseline 2 hours later (Jarome et al., 2011). Thus, the protein degradation changes seen after learning or memory retrieval are likely longer during the consolidation than reconsolidation process. Furthermore, we had found that the time of peak increase in protein degradation following retrieval varied based whether it was a contextual or auditory fear memory. It is possible that following retrieval the protein degradation changes could be temporally controlled based on the brain regions recruited, though this has never been directly tested.

4.2.4. Subcellular localization of protein degradation after retrieval

Some evidence suggests that protein degradation could be localized to synapses following memory retrieval. The first evidence for this came from Lee and colleagues who found increases in degradation-specific protein polyubiquitination in hippocampal crude synaptosomal fractions collected from male mice that had recently undergone contextual fear conditioning (Lee et al., 2008). We reported similar results in the amygdala and, importantly, proteasome function was not reported to be changed in the nuclear or cytoplasmic fractions following fear memory retrieval (Jarome et al., 2011; Orsi et al., 2019). Thus, the evidence, to date, suggests that protein degradation may be largely localized to the synaptic region following memory retrieval, though again it is unclear if this is similar across sexes as the published work used only male rodents.

4.2.5. Targets of protein degradation during reconsolidation

To date, little has been published on the targets of protein degradation during the memory reconsolidation process and our current knowledge of this topic remains the same that it was 10 years ago. In both the amygdala and hippocampus of male rodents, context fear memory retrieval increases the degradation-specific polyubiquitination of SHANK, a major synaptic scaffolding protein, though GKAP, another synaptic scaffold, has also been shown to be a target within the hippocampus (Jarome et al., 2011; Lee et al., 2008). In the amygdala, MOV10, a major component of the RNAi-induced silencing complex (RISC), is also a target (Jarome et al., 2011). Thus, these candidate-driven approaches have identified the same protein targets as those that were suggested during memory consolidation using similar methods. However, it is important to note that in the consolidation literature these candidate-driven targets were not identified as substrates of protein degradation when more sensitive, unbiased methods were used (Farrell et al., 2021). Further, all prior work has been completed in only male rodents. As a result, more work is needed in this area to validate previously identified targets of protein degradation and determine if this varies by sex.

4.3. Protein degradation and sex as a biological variable

As noted above, as our knowledge regarding the role and regulation of protein degradation in memory storage processes has increased this has occurred at the expense of fully understanding sex as a biological variable. However, over the last 2 years evidence has begun to emerge that sex differences do exist in the requirement for protein degradation for the consolidation of some forms of memory, particularly contextual fear conditioning. Based on these recent studies, it is clear that while both males and females need protein degradation in the amygdala to form fear memories, the functional significance of this process differs between sexes. Additionally, females have a unique role of protein degradation in the hippocampus to form contextual fear memories as this is not shared with their male counterparts. While it is unknown why these sex differences exist, some of our prior work suggests that it could be due to inherit baseline differences in the protein degradation process at baseline, at least in the amygdala where females have higher resting levels of proteasome activity and protein polyubiquitination levels (Devulapalli et al., 2021). However, it is unknown why males and females differ in protein degradation at baseline, though it appears to be related to differences in epigenetic regulation of at least one major ubiquitin coding gene, Uba52. Regardless, future studies need to continue this recent trend of incorporating both male and female animals so that a better understanding of how protein degradation is broadly regulating memory can be achieved, especially across brain regions, different behavioral paradigms and stages of memory storage, especially during reconsolidation where, to date, not a single study has been published that has included females.

5. Degradation-independent ubiquitin signaling and memory

While the focus has remained on protein degradation, over the last several years evidence has emerged to support a role for degradation-independent ubiquitin signaling in memory formation. The breadth of this literature is more limited. However, to date, there exists strong evidence supporting a role for proteasome-independent ubiquitin and ubiquitin-like signaling in the process of memory consolidation, though no such evidence has been presented for the reconsolidation process. Here, we will discuss the evidence supporting non-degradation functions of monoubiquitination, linear and K63 polyubiquitination and ubiquitin-like protein SUMOylation in memory consolidation.

5.1. Monoubiquitin

As mentioned earlier, while many proteins are targeted by multiple ubiquitin modifications, i.e., polyubiquitination, others can acquire only a single ubiquitin protein and thus are monoubiquitinated. A variety of cellular processes can be regulated by monoubiquitination, including DNA repair, histone function, receptor endocytosis, and gene expression. Importantly, the proteasome has low affinity for monoubiquitin, meaning that a majority of these protein targets are spared from the degradation process (Hicke, 2001; Sadowski et al., 2012).

The first study to report a role for protein monoubiquitination in memory formation found that the cytoplasmic polyadenylation element binding protein-3 (CPEB3) interacted with Neurl1, a ubiquitin ligase, resulting in monoubiquitination of CPEB3 (Pavlopoulos et al., 2011), a translational activator. By doing so, this monoubiquitination of CPEB3 resulted in increased synthesis of the GluA1 and GluA2 AMPA receptor subunits and the formation of dendritic spines in cultured hippocampal neurons. Further, hippocampal-dependent synaptic plasticity and memory formation were facilitated by Neurl1-mediated monoubiquitination of CPEB3, which occurred via modulation of CPEB3 activity. Thus, this was the first evidence that protein monoubiquitination could regulate synaptic plasticity and memory formation, which in this case was occurring via monoubiquitin-dependent CPEB3 control over protein synthesis and synapse formation.

More recently, we found a novel role of protein monoubiquitination in memory formation via control over the epigenome (Jarome et al., 2021). Specifically, we found that monoubiquitination of histone H2B (H2Bubi), one of the four core histones, was necessary for the recruitment of histone H3 lysine-4 trimethylation (H3K4me4), a major transcriptional activator mark, during contextual fear memory consolidation. Within the hippocampus, H2Bubi loss abolished learning-induced increases in H3K4me3 and gene transcription and impaired synaptic plasticity (LTP) and memory. Additionally, we found that under weak training conditions CRISPR-dCas9-mediated increases in H2Bubi expression promoted H3K4me3 and memory formation. Collectively, these data showed that H2B monoubiquitination regulates histone crosstalk mechanisms necessary for memory formation, opening a new avenue of research into how protein monoubiquitination processes could be involved in memory storage processes. Notable, this was the first direct link between the UPS and epigenetic changes during memory formation, combining two prominent areas of research.

5.2: Linear Polyubiquitination

While there are numerous polyubiquitin modifications that are independent of the proteasome, to date, only two studies have examined the role of proteasome-independent protein polyubiquitination in memory formation. In the first study, we focused on linear (M1) polyubiquitination, the only atypical modification (i.e., lysine independent) that is thought to be completely independent of the protein degradation process (Iwai et al., 2014; Rieser et al., 2013; Spit et al., 2019; Tokunaga et al., 2009). We found that in the amygdala, contextual fear conditioning increased linear (M1) polyubiquitination targeting of proteins in a sex-specific manner (Musaus et al., 2021). Similar to the degradation-specific K48 mark, none of the M1 polyubiquitin targets overlapped between sexes, though in this case the mark had a greater number of protein targets following learning in males than females. Interestingly, the primary target in females was Adiponectin A, a regulator of neuroinflammation, synaptic plasticity and memory, while in males the targets were more equally distributed and generally involved in axonal guidance and cell junction signaling. siRNA-mediated knockdown of Rnf31, an essential part of the linear polyubiquitin E3 complex LUBAC that conjugates off linear polyubiquitin linkages in cells, in the amygdala impaired contextual fear memory consolidation in both sexes. Together, these results suggest that proteasome-independent linear polyubiquitination is critical for memory consolidation in both males and females, though likely has sex-specific functional roles in this process.

5.3. K63 Polyubiquitination

Similar to the M1 linkage site, K63 polyubiquitination, the second most abundant form of ubiquitination in cells, is largely independent of the proteasome. This form of polyubiquitination can instead target proteins for degradation by the lysosome or regulate endocytosis, intracellular trafficking or the DNA damage response (Erpapazoglou et al., 2014; Lee et al., 2017; Nathan et al., 2013). We found that in the amygdala, contextual fear conditioning selectively increased K63 polyubiquitination targeting of proteins in the amygdala (Farrell et al., 2023b). The proteins targeted by K63 polyubiquitination had well described roles in memory formation, including those involved in ATP synthesis, transcription, translation and, surprisingly, proteasome function. CRISPR-dCas13-mediated reductions of K63 polyubiquitination in the amygdala impaired contextual fear memory consolidation in females, but not males, without altering anxiety. Further, inhibition of K63 polyubiquitination in the female amygdala reduced learning-related increases in ATP levels and proteasome activity, the latter linking proteasome-independent polyubiquitination to the protein degradation process. Together, these results suggest that proteasome-independent K63 polyubiquitination is a critical, sex-selective regulator of fear memory formation.

5.4. SUMOylation

In addition to ubiquitination, proteins can also be modified by the small ubiquitin-like modifier (SUMO) via a process called SUMOylation (Celen and Sahin, 2020; Geiss-Friedlander and Melchior, 2007). SUMO proteins are critical for the functioning of eukaryotic cells and there are four paralogues numbered 1 to 4. SUMO1 is structurally different from SUMO2/3, even though they are similar in function and SUMO1 can become a chain terminator for SUMO2/3 polymers. SUMO4, unlike other paralogues, lacks introns, and is found in increasingly high levels after cellular stress. Since it lacks an endogenous protein, SUMO4 has been suggested to be a precursor that might have a role in conjugating target proteins.

SUMOylation occurs in a manner similar to ubiquitination, albeit with some notable differences. The inactive SUMO protein precursors first go through C-terminal cleavage by SENP enzymes. Next, SUMO protein uses an E1 activating enzyme followed by ubiquitin conjugating enzyme 9 (UBC9) to attach SUMO to target substrates. Unlike ubiquitination, proteins can acquire only a single SUMO modification and are never targeted for degradation. Rather, SUMOylation can be involved in a variety of processes that include, but are not limited to, controlling protein stability, subcellular localization, activity and interactions.

Though less studied than ubiquitination, recent evidence does support a role for protein SUMOylation in synaptic plasticity and memory formation. For example, inhibition of SUMOylation impairs LTP and memory for several hippocampus-dependent tasks, including contextual fear conditioning and the Morris water maze (Lee et al., 2014). Overexpression of neuronal SUMO1 impairs contextual fear memory (Matsuzaki et al., 2015), though in another study it was found that neuronal deletion of SUMO1 increases anxiety behaviors and impairs contextual fear memory (Wang et al., 2014). SUMOylation of CREB and SMAD4, a transcription factor that regulates TGFβ signal transduction, has also been shown to be important for memory formation (Chen et al., 2014; Hsu et al., 2017). Interestingly, we recently found that SUMOylation has sex-specific functional roles in the amygdala during the formation of a contextual fear memory (Gustin et al., 2022). Though both male and females had increases in global SUMOylation (2/3) in the amygdala following fear conditioning, proteomic analyses revealed that only females show increased targeting of specific proteins by SUMOylation following learning. When the gene for Ube2i (UBC9), the E2 enzyme responsible for conjugating SUMO to proteins, was knocked down in the amygdala females had enhanced fear memory, while males showed impaired memory retention, an effect that may have been due to compensatory mechanisms in females. Together, these data suggest protein SUMOylation is a critical regulator of memory formation in the brain, though more studies are needed to better understand the conditions under which it positively or negatively regulates the memory consolidation process and how this varies by sex.

5.5. Degradation-independent ubiquitin signaling and sex as a biological variable

Unlike protein degradation, our knowledge regarding the sex-specific roles degradation-independent ubiquitin signaling in memory storage processes is more extensive as most studies have used both male and female rodents, with the exception of those examining monoubiquitination mechanisms. In terms of the latter, future studies will need to test if females share a similar need for monoubiquitination mechanisms during memory formation, which is especially important considering the reported sex differences in proteasome-independent polyubiquitin and ubiquitin-like signaling. Further, future studies need to continue this trend of incorporating both male and female animals as more polyubiquitin mechanisms begin to be examined both within the amygdala and other brain regions.

6. The role of RPT6 in memory formation

Outside of ubiquitin, the RPT6 subunit of the proteasome has been shown to use dual functions to regulate the memory consolidation process. For the canonical function, several studies have shown that phosphorylation of RPT6 is associated with increases in proteasome activity in the amygdala and hippocampus following both behavioral training and memory retrieval (Cullen et al., 2017; Jarome et al., 2016; Jarome et al., 2013). However, this has only been reported in male rodents thus far. Importantly, it has yet to be shown if increases in pRPT6-S120 following training or retrieval are necessary for increases in proteasome function or directly involved in the memory consolidation and reconsolidation processes. One recent study did try to test this using a phosphor-dead knock-in mouse and were unable to observe any behavioral effects (Scudder et al., 2021), though this could be due to compensatory mechanisms induced by the persistent, wide-scale nature of their manipulation that was present throughout all of development. Future studies will be needed to better assess the potential role of RPT6 phosphorylation in proteasome function necessary for memory formation.

Recently, we reported a non-canonical function of RPT6 in which it interacted with H2BubiK120 to regulate changes in histone methylation and gene transcription in the hippocampus during the consolidation of a contextual fear memory (Jarome et al., 2021). As noted above, H2BubiK120 is a non-degradation histone modification that we found was necessary for regulating transcriptionally permissive histone methylation during memory formation. Interestingly, we also found that RPT6 was bound to the same genomic regions as H2BubiK120 following fear conditioning and that knockdown of its coding gene, Psmc5, in the male hippocampus blocked learning-related increases in c-fos histone methylation levels and expression and impaired long-term memory without altering proteasome function. Further, while we recently found that RPT6 does associate with H2BubiK120 in the female hippocampus following contextual fear conditioning, there is no change in RPT6 levels at c-fos, nor did loss of Psmc5 impact learning-related changes in c-fos expression in the female hippocampus (Farrell et al., 2022). Together, these data show that RPT6 has a non-canonical epigenetic function in the hippocampus of both males and females, though is likely targeting different genes during the memory consolidation process.

7. The ubiquitin-proteasome system and memory formation - updating the models

As discussed above, much progress has been made in the last 10 years on elucidating how ubiquitin-proteasome signaling is involved in memory consolidation, though few advances have been made in regards to the reconsolidation process. Currently, the primary model for how ubiquitin-proteasome signaling is contributing to the memory consolidation process is based off our review from a decade ago (Jarome and Helmstetter, 2013), which at the time was based on more limited information using a largely candidate-driven protein identification approach. Further, this original model did not account for sex as a biological variable or proteasome-independent ubiquitin modifications (such as linear or K63 polyubiquitination and SUMOylation) and RPT6 functions outside of the proteasome. Due to this, we now need a more accurate model of how the ubiquitin-proteasome system is regulating memory formation in both males and females, as the recent data suggest that the process is likely different between sexes.

We propose new consolidation models for males (Figure 3) and females (Figure 4) that accounts for the significant advances made in this field over the last 10 years. This new model builds off of the previous by 1) correcting the protein targets and increasing this to a broader network, 2) including new modifications that are degradation-independent, 3) adding the dual functions of RPT6, and 4) accounting for sex as a biological variable. We hope that this updated model will guide advances over the next decade in our understanding of how the ubiquitin-proteasome system regulates memory consolidation in a sex-specific manner. Importantly, from these models we can see that changes in ubiquitin-proteasome activity are likely occurring in both the presynaptic and postsynaptic cell, at least in females, and proteasome-dependent and independent ubiquitin signaling is involved in regulating a wide range of processes critically involved in memory formation, including ATP synthesis, gene transcription including epigenetic modifications, protein translation, proteasome structure and the synaptic structure. Additionally, the proteasome may serve multiple functions during memory formation in both sexes via both protein degradation through the 26S proteasome and epigenetic-mediated transcriptional regulation via the RPT6 subunit. Further, at least in females, proteasome-independent forms of polyubiquitination appear to be involved in regulation of the protein degradation process. Finally, while not depicted in the models due to the limited availability information, these changes, at least in the context of protein degradation, are likely occurring in both neuronal and non-neuronal (astrocytic) cell types. As a result, the evidence collected over the last 25 years is beginning to indicate a broad role for the ubiquitin-proteasome in the regulation of intracellular signaling necessary for learning-dependent synaptic plasticity.

While it is currently unclear why ubiquitin-proteasome signaling is involved in regulating so many molecular processes necessary for memory formation, it is interesting to speculate that this is due to the high expression of the ubiquitin-proteasome machinery throughout all subcellular compartments and in the presynaptic and postsynaptic cells (Adori et al., 2006; Enenkel et al., 1998; Mengual et al., 1996; Speese et al., 2003), the link it has to NMDA-dependent calcium signaling that allows rapid phosphorylation and activation of the proteasome (Bingol and Schuman, 2006; Bingol et al., 2010; Djakovic et al., 2012) and the vast presence of diverse ubiquitin ligases and conjugating enzymes in the cell (Toma-Fukai and Shimizu, 2021). Notable is the highly conserved nature of the UPS where it regulates many of the same molecular processes in other eukaryotic and prokaryotic organisms (Finley et al., 2012; Sadanandom et al., 2012). While not studied in detail, understanding why the UPS appears to be situated to coordinate so many cellular processes necessary for memory formation will be of interest in future studies.

8. The ubiquitin-proteasome system and substance use disorder

There is emerging evidence of UPS dysregulation in psychiatric diseases that engage learning-dependent plasticity such as substance use disorder (SUD). SUD is defined as the compulsive use of psychoactive substances or other chemical agents despite negative consequences (Zou et al., 2017). SUD is a major public health crisis in the U.S. and worldwide, incurring a huge socioeconomic burden. The existing therapies to treat SUD are limited and often fail to provide permanent symptom alleviation. Thus, a better understanding of neuroadaptations underlying SUD is needed to devise more effective therapeutic approaches. Learning and memory is fundamentally integral to SUD, as substances of abuse affect cellular and molecular mechanisms of learning and memory in the brain. These changes underlie compulsive seeking and taking of drugs, and loss of control of drug use, which define SUD (Kauer and Malenka, 2007; Mameli and Luscher, 2011; Nestler, 2013). Transcriptomic and proteomic studies have described the importance of the UPS in SUD (Massaly et al., 2014) and UPS cascades have been shown to govern synaptic and epigenetic plasticity that contribute to behavioral maladaptation inflicted by drugs of abuse. In this section, we will discuss the emerging evidence that ubiquitin-proteasome activity regulates plasticity underlying neuroadaptations associated with drugs of abuse, as well as limitations of our current knowledge and directions for future studies.

8.1. UPS neuroadaptations underlying SUD

8.1.1. Opioids

Opioid use disorder, which is characterized by compulsive opioid taking and high propensity for relapse, has emerged to be one of the critical public health crises of the modern times (Strang et al., 2020). The earliest studies on opioid-mediated UPS regulation were mostly performed in in vitro models. Morphine treatment for 24 h in human neuroblastoma SH-SY5Y cells induces proteasomal degradation of Gβ subunit of heterotrimeric G protein, while an exposure duration of 72 h alters proteasomal Gβ subunits (Neasta et al., 2006). Interestingly, exposure to synthetic opioids, such as DAMGO and DADLE, engage the UPS system differentially. DAMGO has been shown to activate UPS-mediated degradation of RGS4 protein, whereas DADLE elicits μ-opioid receptor (MOR) ubiquitination. An important consideration is that DAMGO has pharmacological specificity towards MOR while DADLE targets δ opioid receptors preferentially, indicating the possibility of discrete UPS mechanisms based on the type of opioid receptor activated. Further, morphine treatment for 48 h in rat C6 glioma cells induces UPS-dependent degradation of glutamate transporter EAAC1 (Yang et al., 2008b). This finding has also been corroborated in vivo whereby intrathecal injection of morphine into the spinal cord for 7 days activated UPS-mediated degradation of glutamate/aspartate transporter (GLAST1 or EAAT1), excitatory amino acid transporter 3 (EAAC1), and glutamate transporter 1 (GLT1) (Yang et al., 2008a). Overall, these data indicate that UPS mechanisms regulate synaptic plasticity following acute or sub-chronic opioid exposure.

Chronic opioid exposure produces varied UPS response depending on drug regimen and paradigm. Morphine treatment for 2 weeks decreases ubiquitin C-terminal hydrolase L-1 in the rat nucleus accumbens (NAc), whereas morphine-induced conditioned place preference (CPP) attenuates α3, α6, β3 β4, β7 subunits, ubiquitin C-terminal hydrolase L1 and ubiquitin-specific protease 7 in the amygdala. Conversely, 4 days of abstinence from morphine treatment increases ubiquitin C-terminal hydrolase L1 and α3 subunit (Lin et al., 2011), which is also observed in the NAc of rhesus monkeys (Bu et al., 2012). It is noteworthy that much of these mechanisms have been examined in males and never been explored in females. Thus, it will be important to investigate how opioids affect UPS activity in a sex-dependent manner.

8.1.2. Methamphetamine

Methamphetamine (METH) is a psychostimulant with a very high abuse potential. High doses of METH in both preclinical models and patients trigger selective degeneration of dopaminergic and serotonergic neuronal terminals in the striatum (Ricaurte et al., 1982; Wilson et al., 1996). While METH neurotoxicity is attributed to oxidative stress, inflammation, mitochondrial dysfunction and excitoxicity, impairments of the UPS have also been reported (Chang et al., 2007; Mirecki et al., 2004; Wilson et al., 1996). An autopsy study of brains from individuals with METH use disorder showed ubiquitin immunoreactive structures in the midbrain, suggesting METH induces UPS dysregulation (Quan et al., 2005). This has further been corroborated in vitro, where METH decreases proteasome activity and promotes aggregation of ubiquitin, α-synuclein and parkin proteins in cultured dopaminergic cells (Fornai et al., 2003; Fornai et al., 2004). Binge METH treatment in adult male rats simultaneously increases 20S proteasome activity, while decreasing 26S proteasome activity, in the striatal synaptosomes (Moszczynska and Yamamoto, 2011). This decrease in 26S proteasomal activity has been linked to oxidative damage of the 19S cap, while the 20S catalytic core is thought to be resistant to oxidative stress, which could be due to the dissociation of the 20S from the 26S core triggered by oxidative stress (Grune et al., 2011; Shang and Taylor, 2011). In contrast to adulthood, the adolescent brain seems to be more resistant to METH neurotoxicity with no METH-induced changes reported in 20S in the nigrostriatal pathway (Cappon et al., 1997; Killinger et al., 2014). It is important to note that these studies were conducted with males, and as such, there are no evidence as to how UPS mechanisms in females is altered due to METH toxicity. Notably, METH exposure induces differential changes in the UPS mechanisms based on the brain region and drug exposure pattern. A number of studies thus far have focused on the intersection of UPS mechanisms and METH-mediated neurotoxicity, leaving a limited understanding of the UPS related to METH dependency, which can be induced at low doses. For example, in the frontal cortex, METH treatment for 8 days increases ubiquitin C-terminal hydrolase L1 and decrease α1, α2 and regulatory 6A subunits, whereas a more than 7 days of abstinence from METH exposure triggers UPS-dependent degradation of SHANK and guanylate kinase-associated protein (GKAP) (Faure et al., 2009; Mao et al., 2009).

8.1.3. Cocaine

Cocaine is a psychoactive substance that blocks dopamine transporter (DAT) leading to buildup of dopamine in the synaptic cleft that is responsible for its euphoric effects. However, the UPS mechanisms that underlie cocaine-induced neuroadaptations remain poorly understood (Nestler, 2005). Cocaine-induced CPP increases ubiquitin conjugating enzyme E2N, α2 and regulatory p45/SUG subunits in the rat medial prefrontal cortex while in the NAc core, increases polyubiquitinated protein levels UPS dependent degradation of N-ethylamaleimide sensitive fusion protein (NSF) protein is augmented (Dietrich et al., 2005; Guan and Guan, 2013; Ren et al., 2013). After cocaine self-administration memory retrieval, we found temporally dynamic UPS responses based on brain region and age of the memory (Werner et al., 2015). Interestingly, UPS-mediated protein degradation in the NAc core was found to be critical for retrieval-induced cocaine memory destabilization, but not for cocaine memory consolidation or retrieval (Ren et al., 2013).

We previously reported that prolonged abstinence from volitional cocaine self-administration induces UPS-mediated degradation of E3 ligases that regulate epigenetic and transcriptional adaptations necessary for expression of cocaine craving (Werner et al., 2018). Following 7, but not 1, days of abstinence, bone morphogenetic pathway (BMP) intermediates SMAD and p-SMAD1/5 are upregulated in the NAc in addition to Ras homolog gene family member (RhoA), a small guanosine triphosphatase (GTPase). RhoA interacts with actin cytoskeleton to influence the plasticity of neurons while p-SMAD1/5 localizes to the nucleus to influence transcriptional mechanisms. This increase of SMAD1/5 is due to decreased K48 ubiquitination via E3 ligase Smurf1, which facilitates the ubiquitin-mediated degradation of SMAD and RhoA. Elevated levels of SMAD1/5 in cocaine-treated animals due to reduced ubiquitin-mediated degradation further facilitated an increased recruitment of transcription factor Runx2. Chromatin immunoprecipitation of Runx2 revealed enrichment of promoter occupancy and transcription of factors such as EGR1, DNML1 and SMARCA4 which have been implicated in cocaine plasticity (Chandra et al., 2017; Chandra et al., 2015). Importantly, EGR3, DNML1 and SMARCA4 have established roles in learning and memory implicating the UPS at the cynosure of cocaine-induced disruption in learning mechanisms (Li et al., 2007; Singh et al., 2018; Zhang et al., 2016).

During prolonged abstinence period of 30 days following extended-access (6 h/session) cocaine self-administration, chromatin remodeler INO80 levels are increased in the nuclear fraction of NAc tissue (Werner et al., 2019). In addition, TRIM3, an E3 ligase that targets INO80 for proteasomal degradation, is also decreased in the nuclear fraction. Furthermore, we also found that INO80 K48 polyubiqutination and INO80-TRIM3 interaction are both reduced. Viral-mediated expression of dominant negative INO80 or WildType TRIM3 in the NAc decreases cue-induced cocaine seeking. It is also noteworthy that INO80 and TRIM3 levels remain unchanged during prolonged abstinence following short-access (1 h/session) cocaine self-administration, as well as during early abstinence following extended-access cocaine self-administration. These findings highlight the importance of drug regimen and abstinence duration in regulating UPS mechanisms. Overall, this study provided insight into the synergy between UPS mechanisms with transcriptional and epigenetic plasticity that underlie behavioral maladaptations induced by cocaine.

8.1.4. Alcohol

Alcohol is a commonly abused substance that can cause severe neurotoxic and cognitive impairments, and causes socioeconomical burdens that include failed relationships and loss of employment. Cultured mouse cortical neurons exposed to ethanol for 5 days exhibit reduced levels of ubiquitin-conjugating enzymes and catalytic and regulatory subunits of the proteasome (Gutala et al., 2004). This finding has been supported another report that found decreased levels of ubiquitin C terminal hydrolase L-1 and ubiquitin conjugating enzyme 7 have been observed in white matter in the brains of individuals with alcohol use disorder (Alexander-Kaufman et al., 2006; Kashem et al., 2007). In a chronic intermittent ethanol (CIE) model of alcohol dependence, genome wide transcriptomic profiling showed that ubiquitin B, ubiquitin conjugating enzymes and ubiquitin peptidases are disrupted in amygdala, hypothalamus and the PFC (Ferguson et al., 2022). Similarly, CIE induces notch signaling ubiquitination in the PFC, however, this is not observed during alcohol abstinence (Melendez et al., 2012). Conversely, acute ethanol exposure in neuroblastoma cells and rat PFC potentiates β-arrestin2 ubiquitination and reduce serotonin 2A receptor internalization that is restored through siRNA knockdown of MDM2 (Luessen et al., 2019). Thus, it can be inferred that dysregulated UPS mechanisms may alter surface expression and trafficking of receptors. In a model that involves 4 months of ethanol exposure, ethanol triggers polyubiquitination of proteins and promotes immunoproteasome activation through induced expression of β2i, β5i and PA28α, while decreasing the 20S constitutive proteasome subunits α2 and β5 (Pla et al., 2014).

Overall, there is accumulating evidence that UPS mechanisms are involved in molecular mechanisms that are targeted by drugs of abuse. Given the abundant evidence that drugs of abuse cause adaptations to cellular and molecular mechanisms involved in learning and memory (Kauer and Malenka, 2007; Mameli and Luscher, 2011; Nestler, 2013), it is possible that many of the UPS-related mechanisms described in previous sections of this review are important for synaptic plasticity that underlies SUD. In addition, there remains very limited knowledge on sex-specific changes and effect on behavioral consequences in SUD, which may be surprising given that it is well-known that SUD affects males and females differently (Becker and Chartoff, 2019; McHugh et al., 2018). Most studies have utilized general proteasomal inhibitors that shut down the entire ubiquitination process or targeted E3 ligases. Advancements in tools to target specific proteasomal subunits will provide deeper insights into how the UPS contributes to the neurobiology that underlies SUD. There remain incredible opportunities to examine how manipulating individual components of the proteasome would produce distinct effects on drug induced behaviors through alteration of epigenetic and/or synaptic plasticity.

9. Conclusions and future directions

Here, we have provided a critical 10 year update on the rapidly emerging evidence suggesting that degradation-dependent and independent ubiquitin-proteasome activity are important regulators of synaptic plasticity underlying memory formation and neuroadaptations associated with drugs of abuse. Additionally, we have provided updated cellular models of how the UPS could be regulating synaptic plasticity in a sex-specific manner during memory formation, an essential modification of models proposed 10 years ago that lacked critical information regarding the importance of sex as a biological variable. These updated models will serve as theoretical framework to guide the next 10 years of studies on the complicated, yet critical role of the UPS in synaptic plasticity underlying memory formation.

Despite the significant advances made in the last decade, there remain significant gaps in our knowledge regarding how ubiquitin-proteasome activity regulates synaptic plasticity underlying memory formation. For example, to date, only 3 of the 8 forms of polyubiquitination have been examined during memory formation. In order to fully understand the ubiquitin code necessary for memory formation, it is imperative that the importance of other forms of polyubiquitination, including K6, K11, K27, K29, and K33 linkage sites, be examined in the memory consolidation process. Further, it is important that future studies begin to elucidate how the use of these different polyubiquitin modifications varies by sex and how they interact to regulate specific cellular pathways necessary for memory formation. Additionally, much more work is needed on the degradation-independent function of proteasome subunits in memory formation as, to date, only RPT6 has been studied and its role remains poorly understood. The involvement of sex hormones in the sex-specific differences in UPS system engagement and usage during memory storage processes are also unknown. Admittedly some technical limitations have slowed the progress on these topics, especially when it comes to quantification and manipulation of diverse polyubiquitin linkage sites. However, such information will be critical to fully understand how the UPS regulates memory formation in a sex-specific manner.

Several studies support the notion that the UPS contributes to synaptic and epigenetic plasticity that contributes to SUD, and yet, large gaps in our understanding remain. Future work should examine how drugs of abuse affect known UPS-related mechanisms of learning and memory, how drugs of abuse affect the UPS system in a sex-specific manner, and how these UPS mechanisms differ based on drug regimen and abstinence period. SUD affects males and females differently (Fox et al., 2014; Hitschfeld et al., 2015; Kennedy et al., 2013; Robbins et al., 1999) and such elucidation would enable a better understanding of the long-term neuroadaptations that underlie the persistent maladaptive learning inflicted by drugs of abuse. Epigenetic modifications are often mediate long-term neuroplastic changes that result from exposure to drugs of abuse, it is essential to investigate how UPS mechanisms act as a cellular bridge between epigenetic and synaptic plasticity. Another important area is the non-degradation polyubiquitination pathways that assign unique functionalities to proteins. These proteasomal-independent mechanisms have never been explored with respect to addictive drugs and warrant further research.

Until recently, the intricacies of UPS cascades that underlie synaptic plasticity related to learning have been stymied due to lack of precise molecular tools. However, the advent of gene editing techniques, such as CRISPR, allow targeting of specific proteasomal subunits and associated proteins. Such manipulations will enable specificity in modifying UPS mechanisms, which will provide deeper insight into the functions of the UPS. Additionally, tools that exhibit cell-type specificity will also open avenues for examining UPS mechanisms in neurons compared to non-neuronal cell-types.

In conclusion, this review has provided an overview of ubiquitin proteasome signaling mechanisms involved activity and learning-dependent synaptic plasticity. Together, the last 25 years of work has provided strong evidence that the UPS is a critical mechanism involved in synaptic plasticity, memory formation and neuroadaptations underlying drugs of abuse, and the next 10 years of research have the potential to uncover exciting new insights on these topics.

Highlights.

Degradation dependent and independent protein polyubiquitination is critical for memory formation
Individual proteasome subunits can function both within and outside of the proteasome complex to regulate memory formation
Sex is a critical variable when assessing the functional significance of ubiquitin-proteasome activity in memory formation and storage
Changes in ubiquitin-proteasome activity underly neuroadapations associated with drugs of abuse

Acknowledgements

This work was supported by National Institutes of Health grants MH122414, MH123742, MH120498, MH120569, MH131587, AG071523 and AG079292 to T.J.J. as well as startup funds from Oklahoma State University Center for Health Sciences (C.T.W.). and Marshall University Research Corporation (S.M.).

Footnotes

Declaration of Interest

Declarations of interest: None

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

Adamsky A, Goshen I, 2018. Astrocytes in Memory Function: Pioneering Findings and Future Directions. Neuroscience 370, 14–26. [DOI] [PubMed] [Google Scholar]
Adamsky A, Kol A, Kreisel T, Doron A, Ozeri-Engelhard N, Melcer T, Refaeli R, Horn H, Regev L, Groysman M, London M, Goshen I, 2018. Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement. Cell 174, 59–71 e14. [DOI] [PubMed] [Google Scholar]
Adori C, Low P, Moszkovkin G, Bagdy G, Laszlo L, Kovacs GG, 2006. Subcellular distribution of components of the ubiquitin-proteasome system in non-diseased human and rat brain. J Histochem Cytochem 54, 263–267. [DOI] [PubMed] [Google Scholar]
Akutsu M, Dikic I, Bremm A, 2016. Ubiquitin chain diversity at a glance. J Cell Sci 129, 875–880. [DOI] [PubMed] [Google Scholar]
Alberini CM, 2005. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci 28, 51–56. [DOI] [PubMed] [Google Scholar]
Alberini CM, 2011. The role of reconsolidation and the dynamic process of long-term memory formation and storage. Front Behav Neurosci 5, 12. [DOI] [PMC free article] [PubMed] [Google Scholar]
Alexander-Kaufman K, James G, Sheedy D, Harper C, Matsumoto I, 2006. Differential protein expression in the prefrontal white matter of human alcoholics: a proteomics study. Mol Psychiatry 11, 56–65. [DOI] [PubMed] [Google Scholar]
Artinian J, McGauran AM, De Jaeger X, Mouledous L, Frances B, Roullet P, 2008. Protein degradation, as with protein synthesis, is required during not only long-term spatial memory consolidation but also reconsolidation. Eur J Neurosci 27, 3009–3019. [DOI] [PubMed] [Google Scholar]
Asok A, Leroy F, Rayman JB, Kandel ER, 2019. Molecular Mechanisms of the Memory Trace. Trends Neurosci 42, 14–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bailey DJ, Kim JJ, Sun W, Thompson RF, Helmstetter FJ, 1999. Acquisition of fear conditioning in rats requires the synthesis of mRNA in the amygdala. Behav Neurosci 113, 276–282. [DOI] [PubMed] [Google Scholar]
Bard JAM, Goodall EA, Greene ER, Jonsson E, Dong KC, Martin A, 2018. Structure and Function of the 26S Proteasome. Annual Review of Biochemistry 87, 697–724. [DOI] [PMC free article] [PubMed] [Google Scholar]
Beamish SB, Gross KS, Anderson MM, Helmstetter FJ, Frick KM, 2022. Sex differences in training-induced activity of the ubiquitin proteasome system in the dorsal hippocampus and medial prefrontal cortex of male and female mice. Learn Mem 29, 302–311. [DOI] [PMC free article] [PubMed] [Google Scholar]
Becker JB, Chartoff E, 2019. Sex differences in neural mechanisms mediating reward and addiction. Neuropsychopharmacology 44, 166–183. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bedford L, Paine S, Sheppard PW, Mayer RJ, Roelofs J, 2010. Assembly, structure, and function of the 26S proteasome. Trends Cell Biol 20, 391–401. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bingol B, Schuman EM, 2006. Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature 441, 1144–1148. [DOI] [PubMed] [Google Scholar]
Bingol B, Wang CF, Arnott D, Cheng D, Peng J, Sheng M, 2010. Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140, 567–578. [DOI] [PubMed] [Google Scholar]
Bu Q, Yang Y, Yan G, Hu Z, Hu C, Duan J, Lv L, Zhou J, Zhao J, Shao X, Deng Y, Li Y, Li H, Zhu R, Zhao Y, Cen X, 2012. Proteomic analysis of the nucleus accumbens in rhesus monkeys of morphine dependence and withdrawal intervention. J Proteomics 75, 1330–1342. [DOI] [PubMed] [Google Scholar]
Cappon GD, Morford LL, Vorhees CV, 1997. Ontogeny of methamphetamine-induced neurotoxicity and associated hyperthermic response. Brain Res Dev Brain Res 103, 155–162. [DOI] [PubMed] [Google Scholar]
Celen AB, Sahin U, 2020. Sumoylation on its 25th anniversary: mechanisms, pathology, and emerging concepts. FEBS J 287, 3110–3140. [DOI] [PubMed] [Google Scholar]
Chain DG, Casadio A, Schacher S, Hegde AN, Valbrun M, Yamamoto N, Goldberg AL, Bartsch D, Kandel ER, Schwartz JH, 1999. Mechanisms for generating the autonomous cAMP-dependent protein kinase required for long-term facilitation in Aplysia. Neuron 22, 147–156. [DOI] [PubMed] [Google Scholar]
Chandra R, Engeln M, Schiefer C, Patton MH, Martin JA, Werner CT, Riggs LM, Francis TC, McGlincy M, Evans B, Nam H, Das S, Girven K, Konkalmatt P, Gancarz AM, Golden SA, Iniguez SD, Russo SJ, Turecki G, Mathur BN, Creed M, Dietz DM, Lobo MK, 2017. Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence. Neuron 96, 1327–1341 e1326. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chandra R, Francis TC, Konkalmatt P, Amgalan A, Gancarz AM, Dietz DM, Lobo MK, 2015. Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action. J Neurosci 35, 7927–7937. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chang L, Alicata D, Ernst T, Volkow N, 2007. Structural and metabolic brain changes in the striatum associated with methamphetamine abuse. Addiction 102 Suppl 1, 16–32. [DOI] [PubMed] [Google Scholar]
Chen YC, Hsu WL, Ma YL, Tai DJ, Lee EH, 2014. CREB SUMOylation by the E3 ligase PIAS1 enhances spatial memory. J Neurosci 34, 9574–9589. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cullen PK, Ferrara NC, Pullins SE, Helmstetter FJ, 2017. Context memory formation requires activity-dependent protein degradation in the hippocampus. Learn Mem 24, 589–596. [DOI] [PMC free article] [PubMed] [Google Scholar]
Devulapalli R, Jones N, Farrell K, Musaus M, Kugler H, McFadden T, Orsi SA, Martin K, Nelsen J, Navabpour S, O’Donnell M, McCoig E, Jarome TJ, 2021. Males and females differ in the regulation and engagement of, but not requirement for, protein degradation in the amygdala during fear memory formation. Neurobiol Learn Mem 180, 107404. [DOI] [PMC free article] [PubMed] [Google Scholar]
Devulapalli RK, Nelsen JL, Orsi SA, McFadden T, Navabpour S, Jones N, Martin K, O’Donnell M, McCoig EL, Jarome TJ, 2019. Males and Females Differ in the Subcellular and Brain Region Dependent Regulation of Proteasome Activity by CaMKII and Protein Kinase A. Neuroscience 418, 1–14. [DOI] [PubMed] [Google Scholar]
Dietrich JB, Mangeol A, Revel MO, Burgun C, Aunis D, Zwiller J, 2005. Acute or repeated cocaine administration generates reactive oxygen species and induces antioxidant enzyme activity in dopaminergic rat brain structures. Neuropharmacology 48, 965–974. [DOI] [PubMed] [Google Scholar]
Djakovic SN, Marquez-Lona EM, Jakawich SK, Wright R, Chu C, Sutton MA, Patrick GN, 2012. Phosphorylation of Rpt6 regulates synaptic strength in hippocampal neurons. J Neurosci 32, 5126–5131. [DOI] [PMC free article] [PubMed] [Google Scholar]
Djakovic SN, Schwarz LA, Barylko B, DeMartino GN, Patrick GN, 2009. Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II. J Biol Chem 284, 26655–26665. [DOI] [PMC free article] [PubMed] [Google Scholar]
Dong C, Bach SV, Haynes KA, Hegde AN, 2014. Proteasome modulates positive and negative translational regulators in long-term synaptic plasticity. J Neurosci 34, 3171–3182. [DOI] [PMC free article] [PubMed] [Google Scholar]
Dong C, Upadhya SC, Ding L, Smith TK, Hegde AN, 2008. Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation. Learn Mem 15, 335–347. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ehlers MD, 2003. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nature neuroscience 6, 231–242. [DOI] [PubMed] [Google Scholar]
Enenkel C, Lehmann A, Kloetzel PM, 1998. Subcellular distribution of proteasomes implicates a major location of protein degradation in the nuclear envelope-ER network in yeast. EMBO J 17, 6144–6154. [DOI] [PMC free article] [PubMed] [Google Scholar]
Erpapazoglou Z, Walker O, Haguenauer-Tsapis R, 2014. Versatile roles of k63-linked ubiquitin chains in trafficking. Cells 3, 1027–1088. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fan XC, Ma CN, Song JC, Liao ZH, Huang N, Liu X, Ma L, 2021. Rac1 Signaling in Amygdala Astrocytes Regulates Fear Memory Acquisition and Retrieval. Neurosci Bull 37, 947–958. [DOI] [PMC free article] [PubMed] [Google Scholar]
Farrell K, Auerbach A, Musaus M, Jarome TJ, 2022. The epigenetic role of proteasome subunit RPT6 during memory formation in female rats. Learn Mem 29, 256–264. [DOI] [PMC free article] [PubMed] [Google Scholar]
Farrell K, McFadden T, Jarome TJ, 2023a. Neuronal and astrocytic protein degradation are critical for fear memory formation. Learn Mem 30, 70–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
Farrell K, Musaus M, Auerbach A, Navabpour S, Ray WK, Helm RF, Jarome TJ, 2023b. Proteasome-independent K63 polyubiquitination selectively regulates ATP levels and proteasome activity during fear memory formation in the female amygdala. Mol Psychiatry. [DOI] [PMC free article] [PubMed] [Google Scholar]
Farrell K, Musaus M, Navabpour S, Martin K, Ray WK, Helm RF, Jarome TJ, 2021. Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation. Front Mol Neurosci 14, 716284. [DOI] [PMC free article] [PubMed] [Google Scholar]
Faure JJ, Hattingh SM, Stein DJ, Daniels WM, 2009. Proteomic analysis reveals differentially expressed proteins in the rat frontal cortex after methamphetamine treatment. Metab Brain Dis 24, 685–700. [DOI] [PubMed] [Google Scholar]
Ferguson LB, Roberts AJ, Mayfield RD, Messing RO, 2022. Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice. PLoS Comput Biol 18, e1009800. [DOI] [PMC free article] [PubMed] [Google Scholar]
Figueiredo LS, Dornelles AS, Petry FS, Falavigna L, Dargel VA, Kobe LM, Aguzzoli C, Roesler R, Schroder N, 2015. Two waves of proteasome-dependent protein degradation in the hippocampus are required for recognition memory consolidation. Neurobiol Learn Mem 120, 1–6. [DOI] [PubMed] [Google Scholar]
Finley D, Ulrich HD, Sommer T, Kaiser P, 2012. The ubiquitin-proteasome system of Saccharomyces cerevisiae. Genetics 192, 319–360. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fonseca R, Vabulas RM, Hartl FU, Bonhoeffer T, Nagerl UV, 2006. A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 52, 239–245. [DOI] [PubMed] [Google Scholar]
Fornai F, Lenzi P, Gesi M, Ferrucci M, Lazzeri G, Busceti CL, Ruffoli R, Soldani P, Ruggieri S, Alessandri MG, Paparelli A, 2003. Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition. J Neurosci 23, 8955–8966. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fornai F, Lenzi P, Gesi M, Soldani P, Ferrucci M, Lazzeri G, Capobianco L, Battaglia G, De Blasi A, Nicoletti F, Paparelli A, 2004. Methamphetamine produces neuronal inclusions in the nigrostriatal system and in PC12 cells. J Neurochem 88, 114–123. [DOI] [PubMed] [Google Scholar]
Fox HC, Morgan PT, Sinha R, 2014. Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals. Neuropsychopharmacology 39, 1527–1537. [DOI] [PMC free article] [PubMed] [Google Scholar]
Furini CR, Myskiw Jde C, Schmidt BE, Zinn CG, Peixoto PB, Pereira LD, Izquierdo I, 2015. The relationship between protein synthesis and protein degradation in object recognition memory. Behav Brain Res 294, 17–24. [DOI] [PubMed] [Google Scholar]
Geiss-Friedlander R, Melchior F, 2007. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8, 947–956. [DOI] [PubMed] [Google Scholar]
Gonzales FR, Howell KK, Dozier LE, Anagnostaras SG, Patrick GN, 2018. Proteasome phosphorylation regulates cocaine-induced sensitization. Mol Cell Neurosci 88, 62–69. [DOI] [PubMed] [Google Scholar]
Grune T, Catalgol B, Licht A, Ermak G, Pickering AM, Ngo JK, Davies KJ, 2011. HSP70 mediates dissociation and reassociation of the 26S proteasome during adaptation to oxidative stress. Free Radic Biol Med 51, 1355–1364. [DOI] [PMC free article] [PubMed] [Google Scholar]
Guan X, Guan Y, 2013. Proteomic profile of differentially expressed proteins in the medial prefrontal cortex after repeated cocaine exposure. Neuroscience 236, 262–270. [DOI] [PubMed] [Google Scholar]
Gustin A, Navabpour S, Farrell K, Martin K, DuVall J, Keith Ray W, Helm RF, Jarome TJ, 2022. Protein SUMOylation is a sex-specific regulator of fear memory formation in the amygdala. Behav Brain Res 430, 113928. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gutala R, Wang J, Kadapakkam S, Hwang Y, Ticku M, Li MD, 2004. Microarray analysis of ethanol-treated cortical neurons reveals disruption of genes related to the ubiquitin-proteasome pathway and protein synthesis. Alcohol Clin Exp Res 28, 1779–1788. [DOI] [PubMed] [Google Scholar]
Hallengren J, Chen PC, Wilson SM, 2013. Neuronal ubiquitin homeostasis. Cell Biochem Biophys 67, 67–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hamilton AM, Oh WC, Vega-Ramirez H, Stein IS, Hell JW, Patrick GN, Zito K, 2012. Activity-dependent growth of new dendritic spines is regulated by the proteasome. Neuron 74, 1023–1030. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hegde AN, 2017. Proteolysis, synaptic plasticity and memory. Neurobiol Learn Mem 138, 98–110. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hegde AN, Goldberg AL, Schwartz JH, 1993. Regulatory subunits of cAMP-dependent protein kinases are degraded after conjugation to ubiquitin: a molecular mechanism underlying long-term synaptic plasticity. Proc Natl Acad Sci U S A 90, 7436–7440. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hegde AN, Haynes KA, Bach SV, Beckelman BC, 2014. Local ubiquitin-proteasome-mediated proteolysis and long-term synaptic plasticity. Front Mol Neurosci 7, 96. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hegde AN, Inokuchi K, Pei W, Casadio A, Ghirardi M, Chain DG, Martin KC, Kandel ER, Schwartz JH, 1997. Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89, 115–126. [DOI] [PubMed] [Google Scholar]
Helmstetter FJ, Parsons RG, Gafford GM, 2008. Macromolecular synthesis, distributed synaptic plasticity, and fear conditioning. Neurobiol Learn Mem 89, 324–337. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hershko A, Ciechanover A, 1998. The ubiquitin system. Annu Rev Biochem 67, 425–479. [DOI] [PubMed] [Google Scholar]
Hicke L, 2001. Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2, 195–201. [DOI] [PubMed] [Google Scholar]
Hitschfeld MJ, Schneekloth TD, Ebbert JO, Hall-Flavin DK, Karpyak VM, Abulseoud OA, Patten CA, Geske JR, Frye MA, 2015. Female smokers have the highest alcohol craving in a residential alcoholism treatment cohort. Drug Alcohol Depend 150, 179–182. [DOI] [PubMed] [Google Scholar]
Hsu WL, Ma YL, Liu YC, Lee EHY, 2017. Smad4 SUMOylation is essential for memory formation through upregulation of the skeletal myopathy gene TPM2. BMC Biol 15, 112. [DOI] [PMC free article] [PubMed] [Google Scholar]
Iwai K, Fujita H, Sasaki Y, 2014. Linear ubiquitin chains: NF-kappaB signalling, cell death and beyond. Nat Rev Mol Cell Biol 15, 503–508. [DOI] [PubMed] [Google Scholar]
Jarome TJ, Ferrara NC, Kwapis JL, Helmstetter FJ, 2015. Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories. Neuropsychopharmacology 40, 3044–3052. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jarome TJ, Ferrara NC, Kwapis JL, Helmstetter FJ, 2016. CaMKII regulates proteasome phosphorylation and activity and promotes memory destabilization following retrieval. Neurobiol Learn Mem 128, 103–109. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jarome TJ, Helmstetter FJ, 2013. The ubiquitin-proteasome system as a critical regulator of synaptic plasticity and long-term memory formation. Neurobiol Learn Mem 105, 107–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jarome TJ, Helmstetter FJ, 2014. Protein degradation and protein synthesis in long-term memory formation. Front Mol Neurosci 7, 61. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jarome TJ, Kwapis JL, Ruenzel WL, Helmstetter FJ, 2013. CaMKII, but not protein kinase A, regulates Rpt6 phosphorylation and proteasome activity during the formation of long-term memories. Front Behav Neurosci 7, 115. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jarome TJ, Perez GA, Webb WM, Hatch KM, Navabpour S, Musaus M, Farrell K, Hauser RM, McFadden T, Martin K, Butler AA, Wang J, Lubin FD, 2021. Ubiquitination of Histone H2B by Proteasome Subunit RPT6 Controls Histone Methylation Chromatin Dynamics During Memory Formation. Biol Psychiatry 89, 1176–1187. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jarome TJ, Werner CT, Kwapis JL, Helmstetter FJ, 2011. Activity dependent protein degradation is critical for the formation and stability of fear memory in the amygdala. PLoS One 6, e24349. [DOI] [PMC free article] [PubMed] [Google Scholar]
Johansen JP, Cain CK, Ostroff LE, LeDoux JE, 2011. Molecular mechanisms of fear learning and memory. Cell 147, 509–524. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kashem MA, James G, Harper C, Wilce P, Matsumoto I, 2007. Differential protein expression in the corpus callosum (splenium) of human alcoholics: a proteomics study. Neurochem Int 50, 450–459. [DOI] [PubMed] [Google Scholar]
Kauer JA, Malenka RC, 2007. Synaptic plasticity and addiction. Nat Rev Neurosci 8, 844–858. [DOI] [PubMed] [Google Scholar]
Kennedy AP, Epstein DH, Phillips KA, Preston KL, 2013. Sex differences in cocaine/heroin users: drug-use triggers and craving in daily life. Drug Alcohol Depend 132, 29–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
Killinger B, Shah M, Moszczynska A, 2014. Co-administration of betulinic acid and methamphetamine causes toxicity to dopaminergic and serotonergic nerve terminals in the striatum of late adolescent rats. J Neurochem 128, 764–775. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kim JJ, Fanselow MS, 1992. Modality-specific retrograde amnesia of fear. Science 256, 675–677. [DOI] [PubMed] [Google Scholar]
Klein ME, Castillo PE, Jordan BA, 2015. Coordination between Translation and Degradation Regulates Inducibility of mGluR-LTD. Cell Rep 10, 1459–1466. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kol A, Adamsky A, Groysman M, Kreisel T, London M, Goshen I, 2020. Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning. Nat Neurosci 23, 1229–1239. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lee BL, Singh A, Mark Glover JN, Hendzel MJ, Spyracopoulos L, 2017. Molecular Basis for K63-Linked Ubiquitination Processes in Double-Strand DNA Break Repair: A Focus on Kinetics and Dynamics. J Mol Biol 429, 3409–3429. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lee JL, 2008. Memory reconsolidation mediates the strengthening of memories by additional learning. Nat Neurosci 11, 1264–1266. [DOI] [PubMed] [Google Scholar]
Lee L, Dale E, Staniszewski A, Zhang H, Saeed F, Sakurai M, Fa M, Orozco I, Michelassi F, Akpan N, Lehrer H, Arancio O, 2014. Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer’s disease. Sci Rep 4, 7190. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lee SH, Choi JH, Lee N, Lee HR, Kim JI, Yu NK, Choi SL, Kim H, Kaang BK, 2008. Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319, 1253–1256. [DOI] [PubMed] [Google Scholar]
Li L, Yun SH, Keblesh J, Trommer BL, Xiong H, Radulovic J, Tourtellotte WG, 2007. Egr3, a synaptic activity regulated transcription factor that is essential for learning and memory. Mol Cell Neurosci 35, 76–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
Li Q, Korte M, Sajikumar S, 2016. Ubiquitin-Proteasome System Inhibition Promotes LongTerm Depression and Synaptic Tagging/Capture. Cereb Cortex 26, 2541–2548. [DOI] [PubMed] [Google Scholar]
Lin X, Wang Q, Cheng Y, Ji J, Yu LC, 2011. Changes of protein expression profiles in the amygdala during the process of morphine-induced conditioned place preference in rats. Behav Brain Res 221, 197–206. [DOI] [PubMed] [Google Scholar]
Lopez-Salon M, Alonso M, Vianna MR, Viola H, Mello e Souza T, Izquierdo I, Pasquini JM, Medina JH, 2001. The ubiquitin-proteasome cascade is required for mammalian long-term memory formation. Eur J Neurosci 14, 1820–1826. [DOI] [PubMed] [Google Scholar]
Luessen DJ, Sun H, McGinnis MM, Hagstrom M, Marrs G, McCool BA, Chen R, 2019. Acute ethanol exposure reduces serotonin receptor 1A internalization by increasing ubiquitination and degradation of beta-arrestin2. J Biol Chem 294, 14068–14080. [DOI] [PMC free article] [PubMed] [Google Scholar]
Mameli M, Luscher C, 2011. Synaptic plasticity and addiction: learning mechanisms gone awry. Neuropharmacology 61, 1052–1059. [DOI] [PubMed] [Google Scholar]
Mamiya N, Fukushima H, Suzuki A, Matsuyama Z, Homma S, Frankland PW, Kida S, 2009. Brain region-specific gene expression activation required for reconsolidation and extinction of contextual fear memory. J Neurosci 29, 402–413. [DOI] [PMC free article] [PubMed] [Google Scholar]
Mao LM, Wang W, Chu XP, Zhang GC, Liu XY, Yang YJ, Haines M, Papasian CJ, Fibuch EE, Buch S, Chen JG, Wang JQ, 2009. Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine. Nature neuroscience 12, 602–610. [DOI] [PMC free article] [PubMed] [Google Scholar]
Marquez-Lona EM, Torres-Machorro AL, Gonzales FR, Pillus L, Patrick GN, 2017. Phosphorylation of the 19S regulatory particle ATPase subunit, Rpt6, modifies susceptibility to proteotoxic stress and protein aggregation. PLoS One 12, e0179893. [DOI] [PMC free article] [PubMed] [Google Scholar]
Martin K, Musaus M, Navabpour S, Gustin A, Ray WK, Helm RF, Jarome TJ, 2021. Females, but not males, require protein degradation in the hippocampus for contextual fear memory formation. Learn Mem 28, 248–253. [DOI] [PMC free article] [PubMed] [Google Scholar]
Massaly N, Dahan L, Baudonnat M, Hovnanian C, Rekik K, Solinas M, David V, Pech S, Zajac JM, Roullet P, Mouledous L, Frances B, 2013. Involvement of protein degradation by the ubiquitin proteasome system in opiate addictive behaviors. Neuropsychopharmacology 38, 596–604. [DOI] [PMC free article] [PubMed] [Google Scholar]
Massaly N, Frances B, Mouledous L, 2014. Roles of the ubiquitin proteasome system in the effects of drugs of abuse. Front Mol Neurosci 7, 99. [DOI] [PMC free article] [PubMed] [Google Scholar]
Matsuzaki S, Lee L, Knock E, Srikumar T, Sakurai M, Hazrati LN, Katayama T, Staniszewski A, Raught B, Arancio O, Fraser PE, 2015. SUMO1 Affects Synaptic Function, Spine Density and Memory. Sci Rep 5, 10730. [DOI] [PMC free article] [PubMed] [Google Scholar]
McGaugh JL, 2015. Consolidating memories. Annu Rev Psychol 66, 1–24. [DOI] [PubMed] [Google Scholar]
McHugh RK, Votaw VR, Sugarman DE, Greenfield SF, 2018. Sex and gender differences in substance use disorders. Clin Psychol Rev 66, 12–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
Melendez RI, McGinty JF, Kalivas PW, Becker HC, 2012. Brain region-specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice. Addict Biol 17, 351–364. [DOI] [PMC free article] [PubMed] [Google Scholar]
Mengual E, Arizti P, Rodrigo J, Gimenez-Amaya JM, Castano JG, 1996. Immunohistochemical distribution and electron microscopic subcellular localization of the proteasome in the rat CNS. J Neurosci 16, 6331–6341. [DOI] [PMC free article] [PubMed] [Google Scholar]
Mirecki A, Fitzmaurice P, Ang L, Kalasinsky KS, Peretti FJ, Aiken SS, Wickham DJ, Sherwin A, Nobrega JN, Forman HJ, Kish SJ, 2004. Brain antioxidant systems in human methamphetamine users. J Neurochem 89, 1396–1408. [DOI] [PubMed] [Google Scholar]
Moszczynska A, Yamamoto BK, 2011. Methamphetamine oxidatively damages parkin and decreases the activity of 26S proteasome in vivo. J Neurochem 116, 1005–1017. [DOI] [PMC free article] [PubMed] [Google Scholar]
Musaus M, Farrell K, Navabpour S, Ray WK, Helm RF, Jarome TJ, 2021. Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation. Front Behav Neurosci 15, 709392. [DOI] [PMC free article] [PubMed] [Google Scholar]
Musaus M, Navabpour S, Jarome TJ, 2020. The diversity of linkage-specific polyubiquitin chains and their role in synaptic plasticity and memory formation. Neurobiol Learn Mem 174, 107286. [DOI] [PMC free article] [PubMed] [Google Scholar]
Nader K, Schafe GE, Le Doux JE, 2000. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726. [DOI] [PubMed] [Google Scholar]
Nathan JA, Kim HT, Ting L, Gygi SP, Goldberg AL, 2013. Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes? Embo j 32, 552–565. [DOI] [PMC free article] [PubMed] [Google Scholar]
Neasta J, Uttenweiler-Joseph S, Chaoui K, Monsarrat B, Meunier JC, Mouledous L, 2006. Effect of long-term exposure of SH-SY5Y cells to morphine: a whole cell proteomic analysis. Proteome Sci 4, 23. [DOI] [PMC free article] [PubMed] [Google Scholar]
Nestler EJ, 2005. The neurobiology of cocaine addiction. Sci Pract Perspect 3, 4–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
Nestler EJ, 2013. Cellular basis of memory for addiction. Dialogues Clin Neurosci 15, 431–443. [DOI] [PMC free article] [PubMed] [Google Scholar]
Orsi SA, Devulapalli RK, Nelsen JL, McFadden T, Surineni R, Jarome TJ, 2019. Distinct subcellular changes in proteasome activity and linkage-specific protein polyubiquitination in the amygdala during the consolidation and reconsolidation of a fear memory. Neurobiol Learn Mem 157, 1–11. [DOI] [PubMed] [Google Scholar]
Park CW, Ryu KY, 2014. Cellular ubiquitin pool dynamics and homeostasis. BMB Rep 47, 475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]
Pavlopoulos E, Trifilieff P, Chevaleyre V, Fioriti L, Zairis S, Pagano A, Malleret G, Kandel ER, 2011. Neuralized1 activates CPEB3: a function for nonproteolytic ubiquitin in synaptic plasticity and memory storage. Cell 147, 1369–1383. [DOI] [PMC free article] [PubMed] [Google Scholar]
Pla A, Pascual M, Renau-Piqueras J, Guerri C, 2014. TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain. Cell Death Dis 5, e1066. [DOI] [PMC free article] [PubMed] [Google Scholar]
Quan L, Ishikawa T, Michiue T, Li DR, Zhao D, Oritani S, Zhu BL, Maeda H, 2005. Ubiquitin-immunoreactive structures in the midbrain of methamphetamine abusers. Leg Med (Tokyo) 7, 144–150. [DOI] [PubMed] [Google Scholar]
Reis DS, Jarome TJ, Helmstetter FJ, 2013. Memory formation for trace fear conditioning requires ubiquitin-proteasome mediated protein degradation in the prefrontal cortex. Front Behav Neurosci 7, 150. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ren ZY, Liu MM, Xue YX, Ding ZB, Xue LF, Zhai SD, Lu L, 2013. A critical role for protein degradation in the nucleus accumbens core in cocaine reward memory. Neuropsychopharmacology 38, 778–790. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ricaurte GA, Guillery RW, Seiden LS, Schuster CR, Moore RY, 1982. Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain. Brain Res 235, 93–103. [DOI] [PubMed] [Google Scholar]
Rieser E, Cordier SM, Walczak H, 2013. Linear ubiquitination: a newly discovered regulator of cell signalling. Trends Biochem Sci 38, 94–102. [DOI] [PubMed] [Google Scholar]
Robbins SJ, Ehrman RN, Childress AR, O’Brien CP, 1999. Comparing levels of cocaine cue reactivity in male and female outpatients. Drug Alcohol Depend 53, 223–230. [DOI] [PubMed] [Google Scholar]
Rodriguez-Ortiz CJ, Balderas I, Saucedo-Alquicira F, Cruz-Castaneda P, Bermudez-Rattoni F, 2011. Long-term aversive taste memory requires insular and amygdala protein degradation. Neurobiol Learn Mem 95, 311–315. [DOI] [PubMed] [Google Scholar]
Rosenberg T, Elkobi A, Dieterich DC, Rosenblum K, 2016a. NMDAR-dependent proteasome activity in the gustatory cortex is necessary for conditioned taste aversion. Neurobiol Learn Mem 130, 7–16. [DOI] [PubMed] [Google Scholar]
Rosenberg T, Elkobi A, Rosenblum K, 2016b. mAChR-dependent decrease in proteasome activity in the gustatory cortex is necessary for novel taste learning. Neurobiol Learn Mem 135, 115–124. [DOI] [PubMed] [Google Scholar]
Sadanandom A, Bailey M, Ewan R, Lee J, Nelis S, 2012. The ubiquitin-proteasome system: central modifier of plant signalling. New Phytol 196, 13–28. [DOI] [PubMed] [Google Scholar]
Sadowski M, Suryadinata R, Tan AR, Roesley SN, Sarcevic B, 2012. Protein monoubiquitination and polyubiquitination generate structural diversity to control distinct biological processes. IUBMB Life 64, 136–142. [DOI] [PubMed] [Google Scholar]
Schafe GE, Nadel NV, Sullivan GM, Harris A, LeDoux JE, 1999. Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn Mem 6, 97–110. [PMC free article] [PubMed] [Google Scholar]
Scudder SL, Gonzales FR, Howell KK, Stein IS, Dozier LE, Anagnostaras SG, Zito K, Patrick GN, 2021. Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning. eNeuro 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
Shang F, Taylor A, 2011. Ubiquitin-proteasome pathway and cellular responses to oxidative stress. Free Radic Biol Med 51, 5–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
Singh M, Denny H, Smith C, Granados J, Renden R, 2018. Presynaptic loss of dynaminrelated protein 1 impairs synaptic vesicle release and recycling at the mouse calyx of Held. J Physiol 596, 6263–6287. [DOI] [PMC free article] [PubMed] [Google Scholar]
Speese SD, Trotta N, Rodesch CK, Aravamudan B, Broadie K, 2003. The ubiquitin proteasome system acutely regulates presynaptic protein turnover and synaptic efficacy. Curr Biol 13, 899–910. [DOI] [PubMed] [Google Scholar]
Spit M, Rieser E, Walczak H, 2019. Linear ubiquitination at a glance. J Cell Sci 132. [DOI] [PubMed] [Google Scholar]
Strang J, Volkow ND, Degenhardt L, Hickman M, Johnson K, Koob GF, Marshall BDL, Tyndall M, Walsh SL, 2020. Opioid use disorder. Nat Rev Dis Primers 6, 3. [DOI] [PubMed] [Google Scholar]
Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S, 2004. Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24, 4787–4795. [DOI] [PMC free article] [PubMed] [Google Scholar]
Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM, 2011. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810–823. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K, 2009. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11, 123–132. [DOI] [PubMed] [Google Scholar]
Toma-Fukai S, Shimizu T, 2021. Structural Diversity of Ubiquitin E3 Ligase. Molecules 26. [DOI] [PMC free article] [PubMed] [Google Scholar]
Vann SD, Aggleton JP, Maguire EA, 2009. What does the retrosplenial cortex do? Nat Rev Neurosci 10, 792–802. [DOI] [PubMed] [Google Scholar]
Wang L, Rodriguiz RM, Wetsel WC, Sheng H, Zhao S, Liu X, Paschen W, Yang W, 2014. Neuron-specific Sumo1–3 knockdown in mice impairs episodic and fear memories. J Psychiatry Neurosci 39, 259–266. [DOI] [PMC free article] [PubMed] [Google Scholar]
Werner CT, Milovanovic M, Christian DT, Loweth JA, Wolf ME, 2015. Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration. Neuropsychopharmacology 40, 3006–3014. [DOI] [PMC free article] [PubMed] [Google Scholar]
Werner CT, Mitra S, Martin JA, Stewart AF, Lepack AE, Ramakrishnan A, Gobira PH, Wang ZJ, Neve RL, Gancarz AM, Shen L, Maze I, Dietz DM, 2019. Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving. Sci Adv 5, eaay0351. [DOI] [PMC free article] [PubMed] [Google Scholar]
Werner CT, Viswanathan R, Martin JA, Gobira PH, Mitra S, Thomas SA, Wang ZJ, Liu JF, Stewart AF, Neve RL, Li JX, Gancarz AM, Dietz DM, 2018. E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking. Biol Psychiatry 84, 881–892. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ, 1996. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2, 699–703. [DOI] [PubMed] [Google Scholar]
Yang L, Wang S, Lim G, Sung B, Zeng Q, Mao J, 2008a. Inhibition of the ubiquitin-proteasome activity prevents glutamate transporter degradation and morphine tolerance. Pain 140, 472–478. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yang L, Wang S, Sung B, Lim G, Mao J, 2008b. Morphine induces ubiquitin-proteasome activity and glutamate transporter degradation. J Biol Chem 283, 21703–21713. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zhang Z, Cao M, Chang CW, Wang C, Shi X, Zhan X, Birnbaum SG, Bezprozvanny I, Huber KM, Wu JI, 2016. Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling. Mol Cell Biol 36, 70–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zou Z, Wang H, d’Oleire Uquillas F, Wang X, Ding J, Chen H, 2017. Definition of Substance and Non-substance Addiction. Adv Exp Med Biol 1010, 21–41. [DOI] [PubMed] [Google Scholar]

[R1] Adamsky A, Goshen I, 2018. Astrocytes in Memory Function: Pioneering Findings and Future Directions. Neuroscience 370, 14–26. [DOI] [PubMed] [Google Scholar]

[R2] Adamsky A, Kol A, Kreisel T, Doron A, Ozeri-Engelhard N, Melcer T, Refaeli R, Horn H, Regev L, Groysman M, London M, Goshen I, 2018. Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement. Cell 174, 59–71 e14. [DOI] [PubMed] [Google Scholar]

[R3] Adori C, Low P, Moszkovkin G, Bagdy G, Laszlo L, Kovacs GG, 2006. Subcellular distribution of components of the ubiquitin-proteasome system in non-diseased human and rat brain. J Histochem Cytochem 54, 263–267. [DOI] [PubMed] [Google Scholar]

[R4] Akutsu M, Dikic I, Bremm A, 2016. Ubiquitin chain diversity at a glance. J Cell Sci 129, 875–880. [DOI] [PubMed] [Google Scholar]

[R5] Alberini CM, 2005. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci 28, 51–56. [DOI] [PubMed] [Google Scholar]

[R6] Alberini CM, 2011. The role of reconsolidation and the dynamic process of long-term memory formation and storage. Front Behav Neurosci 5, 12. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] Alexander-Kaufman K, James G, Sheedy D, Harper C, Matsumoto I, 2006. Differential protein expression in the prefrontal white matter of human alcoholics: a proteomics study. Mol Psychiatry 11, 56–65. [DOI] [PubMed] [Google Scholar]

[R8] Artinian J, McGauran AM, De Jaeger X, Mouledous L, Frances B, Roullet P, 2008. Protein degradation, as with protein synthesis, is required during not only long-term spatial memory consolidation but also reconsolidation. Eur J Neurosci 27, 3009–3019. [DOI] [PubMed] [Google Scholar]

[R9] Asok A, Leroy F, Rayman JB, Kandel ER, 2019. Molecular Mechanisms of the Memory Trace. Trends Neurosci 42, 14–22. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R10] Bailey DJ, Kim JJ, Sun W, Thompson RF, Helmstetter FJ, 1999. Acquisition of fear conditioning in rats requires the synthesis of mRNA in the amygdala. Behav Neurosci 113, 276–282. [DOI] [PubMed] [Google Scholar]

[R11] Bard JAM, Goodall EA, Greene ER, Jonsson E, Dong KC, Martin A, 2018. Structure and Function of the 26S Proteasome. Annual Review of Biochemistry 87, 697–724. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R12] Beamish SB, Gross KS, Anderson MM, Helmstetter FJ, Frick KM, 2022. Sex differences in training-induced activity of the ubiquitin proteasome system in the dorsal hippocampus and medial prefrontal cortex of male and female mice. Learn Mem 29, 302–311. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R13] Becker JB, Chartoff E, 2019. Sex differences in neural mechanisms mediating reward and addiction. Neuropsychopharmacology 44, 166–183. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R14] Bedford L, Paine S, Sheppard PW, Mayer RJ, Roelofs J, 2010. Assembly, structure, and function of the 26S proteasome. Trends Cell Biol 20, 391–401. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R15] Bingol B, Schuman EM, 2006. Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature 441, 1144–1148. [DOI] [PubMed] [Google Scholar]

[R16] Bingol B, Wang CF, Arnott D, Cheng D, Peng J, Sheng M, 2010. Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140, 567–578. [DOI] [PubMed] [Google Scholar]

[R17] Bu Q, Yang Y, Yan G, Hu Z, Hu C, Duan J, Lv L, Zhou J, Zhao J, Shao X, Deng Y, Li Y, Li H, Zhu R, Zhao Y, Cen X, 2012. Proteomic analysis of the nucleus accumbens in rhesus monkeys of morphine dependence and withdrawal intervention. J Proteomics 75, 1330–1342. [DOI] [PubMed] [Google Scholar]

[R18] Cappon GD, Morford LL, Vorhees CV, 1997. Ontogeny of methamphetamine-induced neurotoxicity and associated hyperthermic response. Brain Res Dev Brain Res 103, 155–162. [DOI] [PubMed] [Google Scholar]

[R19] Celen AB, Sahin U, 2020. Sumoylation on its 25th anniversary: mechanisms, pathology, and emerging concepts. FEBS J 287, 3110–3140. [DOI] [PubMed] [Google Scholar]

[R20] Chain DG, Casadio A, Schacher S, Hegde AN, Valbrun M, Yamamoto N, Goldberg AL, Bartsch D, Kandel ER, Schwartz JH, 1999. Mechanisms for generating the autonomous cAMP-dependent protein kinase required for long-term facilitation in Aplysia. Neuron 22, 147–156. [DOI] [PubMed] [Google Scholar]

[R21] Chandra R, Engeln M, Schiefer C, Patton MH, Martin JA, Werner CT, Riggs LM, Francis TC, McGlincy M, Evans B, Nam H, Das S, Girven K, Konkalmatt P, Gancarz AM, Golden SA, Iniguez SD, Russo SJ, Turecki G, Mathur BN, Creed M, Dietz DM, Lobo MK, 2017. Drp1 Mitochondrial Fission in D1 Neurons Mediates Behavioral and Cellular Plasticity during Early Cocaine Abstinence. Neuron 96, 1327–1341 e1326. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R22] Chandra R, Francis TC, Konkalmatt P, Amgalan A, Gancarz AM, Dietz DM, Lobo MK, 2015. Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action. J Neurosci 35, 7927–7937. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R23] Chang L, Alicata D, Ernst T, Volkow N, 2007. Structural and metabolic brain changes in the striatum associated with methamphetamine abuse. Addiction 102 Suppl 1, 16–32. [DOI] [PubMed] [Google Scholar]

[R24] Chen YC, Hsu WL, Ma YL, Tai DJ, Lee EH, 2014. CREB SUMOylation by the E3 ligase PIAS1 enhances spatial memory. J Neurosci 34, 9574–9589. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R25] Cullen PK, Ferrara NC, Pullins SE, Helmstetter FJ, 2017. Context memory formation requires activity-dependent protein degradation in the hippocampus. Learn Mem 24, 589–596. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R26] Devulapalli R, Jones N, Farrell K, Musaus M, Kugler H, McFadden T, Orsi SA, Martin K, Nelsen J, Navabpour S, O’Donnell M, McCoig E, Jarome TJ, 2021. Males and females differ in the regulation and engagement of, but not requirement for, protein degradation in the amygdala during fear memory formation. Neurobiol Learn Mem 180, 107404. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R27] Devulapalli RK, Nelsen JL, Orsi SA, McFadden T, Navabpour S, Jones N, Martin K, O’Donnell M, McCoig EL, Jarome TJ, 2019. Males and Females Differ in the Subcellular and Brain Region Dependent Regulation of Proteasome Activity by CaMKII and Protein Kinase A. Neuroscience 418, 1–14. [DOI] [PubMed] [Google Scholar]

[R28] Dietrich JB, Mangeol A, Revel MO, Burgun C, Aunis D, Zwiller J, 2005. Acute or repeated cocaine administration generates reactive oxygen species and induces antioxidant enzyme activity in dopaminergic rat brain structures. Neuropharmacology 48, 965–974. [DOI] [PubMed] [Google Scholar]

[R29] Djakovic SN, Marquez-Lona EM, Jakawich SK, Wright R, Chu C, Sutton MA, Patrick GN, 2012. Phosphorylation of Rpt6 regulates synaptic strength in hippocampal neurons. J Neurosci 32, 5126–5131. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] Djakovic SN, Schwarz LA, Barylko B, DeMartino GN, Patrick GN, 2009. Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II. J Biol Chem 284, 26655–26665. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R31] Dong C, Bach SV, Haynes KA, Hegde AN, 2014. Proteasome modulates positive and negative translational regulators in long-term synaptic plasticity. J Neurosci 34, 3171–3182. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] Dong C, Upadhya SC, Ding L, Smith TK, Hegde AN, 2008. Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation. Learn Mem 15, 335–347. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R33] Ehlers MD, 2003. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nature neuroscience 6, 231–242. [DOI] [PubMed] [Google Scholar]

[R34] Enenkel C, Lehmann A, Kloetzel PM, 1998. Subcellular distribution of proteasomes implicates a major location of protein degradation in the nuclear envelope-ER network in yeast. EMBO J 17, 6144–6154. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R35] Erpapazoglou Z, Walker O, Haguenauer-Tsapis R, 2014. Versatile roles of k63-linked ubiquitin chains in trafficking. Cells 3, 1027–1088. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R36] Fan XC, Ma CN, Song JC, Liao ZH, Huang N, Liu X, Ma L, 2021. Rac1 Signaling in Amygdala Astrocytes Regulates Fear Memory Acquisition and Retrieval. Neurosci Bull 37, 947–958. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R37] Farrell K, Auerbach A, Musaus M, Jarome TJ, 2022. The epigenetic role of proteasome subunit RPT6 during memory formation in female rats. Learn Mem 29, 256–264. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] Farrell K, McFadden T, Jarome TJ, 2023a. Neuronal and astrocytic protein degradation are critical for fear memory formation. Learn Mem 30, 70–73. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R39] Farrell K, Musaus M, Auerbach A, Navabpour S, Ray WK, Helm RF, Jarome TJ, 2023b. Proteasome-independent K63 polyubiquitination selectively regulates ATP levels and proteasome activity during fear memory formation in the female amygdala. Mol Psychiatry. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R40] Farrell K, Musaus M, Navabpour S, Martin K, Ray WK, Helm RF, Jarome TJ, 2021. Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation. Front Mol Neurosci 14, 716284. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R41] Faure JJ, Hattingh SM, Stein DJ, Daniels WM, 2009. Proteomic analysis reveals differentially expressed proteins in the rat frontal cortex after methamphetamine treatment. Metab Brain Dis 24, 685–700. [DOI] [PubMed] [Google Scholar]

[R42] Ferguson LB, Roberts AJ, Mayfield RD, Messing RO, 2022. Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice. PLoS Comput Biol 18, e1009800. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R43] Figueiredo LS, Dornelles AS, Petry FS, Falavigna L, Dargel VA, Kobe LM, Aguzzoli C, Roesler R, Schroder N, 2015. Two waves of proteasome-dependent protein degradation in the hippocampus are required for recognition memory consolidation. Neurobiol Learn Mem 120, 1–6. [DOI] [PubMed] [Google Scholar]

[R44] Finley D, Ulrich HD, Sommer T, Kaiser P, 2012. The ubiquitin-proteasome system of Saccharomyces cerevisiae. Genetics 192, 319–360. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R45] Fonseca R, Vabulas RM, Hartl FU, Bonhoeffer T, Nagerl UV, 2006. A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 52, 239–245. [DOI] [PubMed] [Google Scholar]

[R46] Fornai F, Lenzi P, Gesi M, Ferrucci M, Lazzeri G, Busceti CL, Ruffoli R, Soldani P, Ruggieri S, Alessandri MG, Paparelli A, 2003. Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition. J Neurosci 23, 8955–8966. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R47] Fornai F, Lenzi P, Gesi M, Soldani P, Ferrucci M, Lazzeri G, Capobianco L, Battaglia G, De Blasi A, Nicoletti F, Paparelli A, 2004. Methamphetamine produces neuronal inclusions in the nigrostriatal system and in PC12 cells. J Neurochem 88, 114–123. [DOI] [PubMed] [Google Scholar]

[R48] Fox HC, Morgan PT, Sinha R, 2014. Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals. Neuropsychopharmacology 39, 1527–1537. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R49] Furini CR, Myskiw Jde C, Schmidt BE, Zinn CG, Peixoto PB, Pereira LD, Izquierdo I, 2015. The relationship between protein synthesis and protein degradation in object recognition memory. Behav Brain Res 294, 17–24. [DOI] [PubMed] [Google Scholar]

[R50] Geiss-Friedlander R, Melchior F, 2007. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8, 947–956. [DOI] [PubMed] [Google Scholar]

[R51] Gonzales FR, Howell KK, Dozier LE, Anagnostaras SG, Patrick GN, 2018. Proteasome phosphorylation regulates cocaine-induced sensitization. Mol Cell Neurosci 88, 62–69. [DOI] [PubMed] [Google Scholar]

[R52] Grune T, Catalgol B, Licht A, Ermak G, Pickering AM, Ngo JK, Davies KJ, 2011. HSP70 mediates dissociation and reassociation of the 26S proteasome during adaptation to oxidative stress. Free Radic Biol Med 51, 1355–1364. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R53] Guan X, Guan Y, 2013. Proteomic profile of differentially expressed proteins in the medial prefrontal cortex after repeated cocaine exposure. Neuroscience 236, 262–270. [DOI] [PubMed] [Google Scholar]

[R54] Gustin A, Navabpour S, Farrell K, Martin K, DuVall J, Keith Ray W, Helm RF, Jarome TJ, 2022. Protein SUMOylation is a sex-specific regulator of fear memory formation in the amygdala. Behav Brain Res 430, 113928. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R55] Gutala R, Wang J, Kadapakkam S, Hwang Y, Ticku M, Li MD, 2004. Microarray analysis of ethanol-treated cortical neurons reveals disruption of genes related to the ubiquitin-proteasome pathway and protein synthesis. Alcohol Clin Exp Res 28, 1779–1788. [DOI] [PubMed] [Google Scholar]

[R56] Hallengren J, Chen PC, Wilson SM, 2013. Neuronal ubiquitin homeostasis. Cell Biochem Biophys 67, 67–73. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R57] Hamilton AM, Oh WC, Vega-Ramirez H, Stein IS, Hell JW, Patrick GN, Zito K, 2012. Activity-dependent growth of new dendritic spines is regulated by the proteasome. Neuron 74, 1023–1030. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R58] Hegde AN, 2017. Proteolysis, synaptic plasticity and memory. Neurobiol Learn Mem 138, 98–110. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R59] Hegde AN, Goldberg AL, Schwartz JH, 1993. Regulatory subunits of cAMP-dependent protein kinases are degraded after conjugation to ubiquitin: a molecular mechanism underlying long-term synaptic plasticity. Proc Natl Acad Sci U S A 90, 7436–7440. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R60] Hegde AN, Haynes KA, Bach SV, Beckelman BC, 2014. Local ubiquitin-proteasome-mediated proteolysis and long-term synaptic plasticity. Front Mol Neurosci 7, 96. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R61] Hegde AN, Inokuchi K, Pei W, Casadio A, Ghirardi M, Chain DG, Martin KC, Kandel ER, Schwartz JH, 1997. Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89, 115–126. [DOI] [PubMed] [Google Scholar]

[R62] Helmstetter FJ, Parsons RG, Gafford GM, 2008. Macromolecular synthesis, distributed synaptic plasticity, and fear conditioning. Neurobiol Learn Mem 89, 324–337. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R63] Hershko A, Ciechanover A, 1998. The ubiquitin system. Annu Rev Biochem 67, 425–479. [DOI] [PubMed] [Google Scholar]

[R64] Hicke L, 2001. Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2, 195–201. [DOI] [PubMed] [Google Scholar]

[R65] Hitschfeld MJ, Schneekloth TD, Ebbert JO, Hall-Flavin DK, Karpyak VM, Abulseoud OA, Patten CA, Geske JR, Frye MA, 2015. Female smokers have the highest alcohol craving in a residential alcoholism treatment cohort. Drug Alcohol Depend 150, 179–182. [DOI] [PubMed] [Google Scholar]

[R66] Hsu WL, Ma YL, Liu YC, Lee EHY, 2017. Smad4 SUMOylation is essential for memory formation through upregulation of the skeletal myopathy gene TPM2. BMC Biol 15, 112. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R67] Iwai K, Fujita H, Sasaki Y, 2014. Linear ubiquitin chains: NF-kappaB signalling, cell death and beyond. Nat Rev Mol Cell Biol 15, 503–508. [DOI] [PubMed] [Google Scholar]

[R68] Jarome TJ, Ferrara NC, Kwapis JL, Helmstetter FJ, 2015. Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories. Neuropsychopharmacology 40, 3044–3052. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R69] Jarome TJ, Ferrara NC, Kwapis JL, Helmstetter FJ, 2016. CaMKII regulates proteasome phosphorylation and activity and promotes memory destabilization following retrieval. Neurobiol Learn Mem 128, 103–109. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R70] Jarome TJ, Helmstetter FJ, 2013. The ubiquitin-proteasome system as a critical regulator of synaptic plasticity and long-term memory formation. Neurobiol Learn Mem 105, 107–116. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R71] Jarome TJ, Helmstetter FJ, 2014. Protein degradation and protein synthesis in long-term memory formation. Front Mol Neurosci 7, 61. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R72] Jarome TJ, Kwapis JL, Ruenzel WL, Helmstetter FJ, 2013. CaMKII, but not protein kinase A, regulates Rpt6 phosphorylation and proteasome activity during the formation of long-term memories. Front Behav Neurosci 7, 115. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R73] Jarome TJ, Perez GA, Webb WM, Hatch KM, Navabpour S, Musaus M, Farrell K, Hauser RM, McFadden T, Martin K, Butler AA, Wang J, Lubin FD, 2021. Ubiquitination of Histone H2B by Proteasome Subunit RPT6 Controls Histone Methylation Chromatin Dynamics During Memory Formation. Biol Psychiatry 89, 1176–1187. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R74] Jarome TJ, Werner CT, Kwapis JL, Helmstetter FJ, 2011. Activity dependent protein degradation is critical for the formation and stability of fear memory in the amygdala. PLoS One 6, e24349. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R75] Johansen JP, Cain CK, Ostroff LE, LeDoux JE, 2011. Molecular mechanisms of fear learning and memory. Cell 147, 509–524. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R76] Kashem MA, James G, Harper C, Wilce P, Matsumoto I, 2007. Differential protein expression in the corpus callosum (splenium) of human alcoholics: a proteomics study. Neurochem Int 50, 450–459. [DOI] [PubMed] [Google Scholar]

[R77] Kauer JA, Malenka RC, 2007. Synaptic plasticity and addiction. Nat Rev Neurosci 8, 844–858. [DOI] [PubMed] [Google Scholar]

[R78] Kennedy AP, Epstein DH, Phillips KA, Preston KL, 2013. Sex differences in cocaine/heroin users: drug-use triggers and craving in daily life. Drug Alcohol Depend 132, 29–37. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R79] Killinger B, Shah M, Moszczynska A, 2014. Co-administration of betulinic acid and methamphetamine causes toxicity to dopaminergic and serotonergic nerve terminals in the striatum of late adolescent rats. J Neurochem 128, 764–775. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R80] Kim JJ, Fanselow MS, 1992. Modality-specific retrograde amnesia of fear. Science 256, 675–677. [DOI] [PubMed] [Google Scholar]

[R81] Klein ME, Castillo PE, Jordan BA, 2015. Coordination between Translation and Degradation Regulates Inducibility of mGluR-LTD. Cell Rep 10, 1459–1466. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R82] Kol A, Adamsky A, Groysman M, Kreisel T, London M, Goshen I, 2020. Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning. Nat Neurosci 23, 1229–1239. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R83] Lee BL, Singh A, Mark Glover JN, Hendzel MJ, Spyracopoulos L, 2017. Molecular Basis for K63-Linked Ubiquitination Processes in Double-Strand DNA Break Repair: A Focus on Kinetics and Dynamics. J Mol Biol 429, 3409–3429. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R84] Lee JL, 2008. Memory reconsolidation mediates the strengthening of memories by additional learning. Nat Neurosci 11, 1264–1266. [DOI] [PubMed] [Google Scholar]

[R85] Lee L, Dale E, Staniszewski A, Zhang H, Saeed F, Sakurai M, Fa M, Orozco I, Michelassi F, Akpan N, Lehrer H, Arancio O, 2014. Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer’s disease. Sci Rep 4, 7190. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R86] Lee SH, Choi JH, Lee N, Lee HR, Kim JI, Yu NK, Choi SL, Kim H, Kaang BK, 2008. Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319, 1253–1256. [DOI] [PubMed] [Google Scholar]

[R87] Li L, Yun SH, Keblesh J, Trommer BL, Xiong H, Radulovic J, Tourtellotte WG, 2007. Egr3, a synaptic activity regulated transcription factor that is essential for learning and memory. Mol Cell Neurosci 35, 76–88. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R88] Li Q, Korte M, Sajikumar S, 2016. Ubiquitin-Proteasome System Inhibition Promotes LongTerm Depression and Synaptic Tagging/Capture. Cereb Cortex 26, 2541–2548. [DOI] [PubMed] [Google Scholar]

[R89] Lin X, Wang Q, Cheng Y, Ji J, Yu LC, 2011. Changes of protein expression profiles in the amygdala during the process of morphine-induced conditioned place preference in rats. Behav Brain Res 221, 197–206. [DOI] [PubMed] [Google Scholar]

[R90] Lopez-Salon M, Alonso M, Vianna MR, Viola H, Mello e Souza T, Izquierdo I, Pasquini JM, Medina JH, 2001. The ubiquitin-proteasome cascade is required for mammalian long-term memory formation. Eur J Neurosci 14, 1820–1826. [DOI] [PubMed] [Google Scholar]

[R91] Luessen DJ, Sun H, McGinnis MM, Hagstrom M, Marrs G, McCool BA, Chen R, 2019. Acute ethanol exposure reduces serotonin receptor 1A internalization by increasing ubiquitination and degradation of beta-arrestin2. J Biol Chem 294, 14068–14080. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R92] Mameli M, Luscher C, 2011. Synaptic plasticity and addiction: learning mechanisms gone awry. Neuropharmacology 61, 1052–1059. [DOI] [PubMed] [Google Scholar]

[R93] Mamiya N, Fukushima H, Suzuki A, Matsuyama Z, Homma S, Frankland PW, Kida S, 2009. Brain region-specific gene expression activation required for reconsolidation and extinction of contextual fear memory. J Neurosci 29, 402–413. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R94] Mao LM, Wang W, Chu XP, Zhang GC, Liu XY, Yang YJ, Haines M, Papasian CJ, Fibuch EE, Buch S, Chen JG, Wang JQ, 2009. Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine. Nature neuroscience 12, 602–610. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R95] Marquez-Lona EM, Torres-Machorro AL, Gonzales FR, Pillus L, Patrick GN, 2017. Phosphorylation of the 19S regulatory particle ATPase subunit, Rpt6, modifies susceptibility to proteotoxic stress and protein aggregation. PLoS One 12, e0179893. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R96] Martin K, Musaus M, Navabpour S, Gustin A, Ray WK, Helm RF, Jarome TJ, 2021. Females, but not males, require protein degradation in the hippocampus for contextual fear memory formation. Learn Mem 28, 248–253. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R97] Massaly N, Dahan L, Baudonnat M, Hovnanian C, Rekik K, Solinas M, David V, Pech S, Zajac JM, Roullet P, Mouledous L, Frances B, 2013. Involvement of protein degradation by the ubiquitin proteasome system in opiate addictive behaviors. Neuropsychopharmacology 38, 596–604. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R98] Massaly N, Frances B, Mouledous L, 2014. Roles of the ubiquitin proteasome system in the effects of drugs of abuse. Front Mol Neurosci 7, 99. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R99] Matsuzaki S, Lee L, Knock E, Srikumar T, Sakurai M, Hazrati LN, Katayama T, Staniszewski A, Raught B, Arancio O, Fraser PE, 2015. SUMO1 Affects Synaptic Function, Spine Density and Memory. Sci Rep 5, 10730. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R100] McGaugh JL, 2015. Consolidating memories. Annu Rev Psychol 66, 1–24. [DOI] [PubMed] [Google Scholar]

[R101] McHugh RK, Votaw VR, Sugarman DE, Greenfield SF, 2018. Sex and gender differences in substance use disorders. Clin Psychol Rev 66, 12–23. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R102] Melendez RI, McGinty JF, Kalivas PW, Becker HC, 2012. Brain region-specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice. Addict Biol 17, 351–364. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R103] Mengual E, Arizti P, Rodrigo J, Gimenez-Amaya JM, Castano JG, 1996. Immunohistochemical distribution and electron microscopic subcellular localization of the proteasome in the rat CNS. J Neurosci 16, 6331–6341. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R104] Mirecki A, Fitzmaurice P, Ang L, Kalasinsky KS, Peretti FJ, Aiken SS, Wickham DJ, Sherwin A, Nobrega JN, Forman HJ, Kish SJ, 2004. Brain antioxidant systems in human methamphetamine users. J Neurochem 89, 1396–1408. [DOI] [PubMed] [Google Scholar]

[R105] Moszczynska A, Yamamoto BK, 2011. Methamphetamine oxidatively damages parkin and decreases the activity of 26S proteasome in vivo. J Neurochem 116, 1005–1017. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R106] Musaus M, Farrell K, Navabpour S, Ray WK, Helm RF, Jarome TJ, 2021. Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation. Front Behav Neurosci 15, 709392. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R107] Musaus M, Navabpour S, Jarome TJ, 2020. The diversity of linkage-specific polyubiquitin chains and their role in synaptic plasticity and memory formation. Neurobiol Learn Mem 174, 107286. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R108] Nader K, Schafe GE, Le Doux JE, 2000. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726. [DOI] [PubMed] [Google Scholar]

[R109] Nathan JA, Kim HT, Ting L, Gygi SP, Goldberg AL, 2013. Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes? Embo j 32, 552–565. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R110] Neasta J, Uttenweiler-Joseph S, Chaoui K, Monsarrat B, Meunier JC, Mouledous L, 2006. Effect of long-term exposure of SH-SY5Y cells to morphine: a whole cell proteomic analysis. Proteome Sci 4, 23. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R111] Nestler EJ, 2005. The neurobiology of cocaine addiction. Sci Pract Perspect 3, 4–10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R112] Nestler EJ, 2013. Cellular basis of memory for addiction. Dialogues Clin Neurosci 15, 431–443. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R113] Orsi SA, Devulapalli RK, Nelsen JL, McFadden T, Surineni R, Jarome TJ, 2019. Distinct subcellular changes in proteasome activity and linkage-specific protein polyubiquitination in the amygdala during the consolidation and reconsolidation of a fear memory. Neurobiol Learn Mem 157, 1–11. [DOI] [PubMed] [Google Scholar]

[R114] Park CW, Ryu KY, 2014. Cellular ubiquitin pool dynamics and homeostasis. BMB Rep 47, 475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R115] Pavlopoulos E, Trifilieff P, Chevaleyre V, Fioriti L, Zairis S, Pagano A, Malleret G, Kandel ER, 2011. Neuralized1 activates CPEB3: a function for nonproteolytic ubiquitin in synaptic plasticity and memory storage. Cell 147, 1369–1383. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R116] Pla A, Pascual M, Renau-Piqueras J, Guerri C, 2014. TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain. Cell Death Dis 5, e1066. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R117] Quan L, Ishikawa T, Michiue T, Li DR, Zhao D, Oritani S, Zhu BL, Maeda H, 2005. Ubiquitin-immunoreactive structures in the midbrain of methamphetamine abusers. Leg Med (Tokyo) 7, 144–150. [DOI] [PubMed] [Google Scholar]

[R118] Reis DS, Jarome TJ, Helmstetter FJ, 2013. Memory formation for trace fear conditioning requires ubiquitin-proteasome mediated protein degradation in the prefrontal cortex. Front Behav Neurosci 7, 150. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R119] Ren ZY, Liu MM, Xue YX, Ding ZB, Xue LF, Zhai SD, Lu L, 2013. A critical role for protein degradation in the nucleus accumbens core in cocaine reward memory. Neuropsychopharmacology 38, 778–790. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R120] Ricaurte GA, Guillery RW, Seiden LS, Schuster CR, Moore RY, 1982. Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain. Brain Res 235, 93–103. [DOI] [PubMed] [Google Scholar]

[R121] Rieser E, Cordier SM, Walczak H, 2013. Linear ubiquitination: a newly discovered regulator of cell signalling. Trends Biochem Sci 38, 94–102. [DOI] [PubMed] [Google Scholar]

[R122] Robbins SJ, Ehrman RN, Childress AR, O’Brien CP, 1999. Comparing levels of cocaine cue reactivity in male and female outpatients. Drug Alcohol Depend 53, 223–230. [DOI] [PubMed] [Google Scholar]

[R123] Rodriguez-Ortiz CJ, Balderas I, Saucedo-Alquicira F, Cruz-Castaneda P, Bermudez-Rattoni F, 2011. Long-term aversive taste memory requires insular and amygdala protein degradation. Neurobiol Learn Mem 95, 311–315. [DOI] [PubMed] [Google Scholar]

[R124] Rosenberg T, Elkobi A, Dieterich DC, Rosenblum K, 2016a. NMDAR-dependent proteasome activity in the gustatory cortex is necessary for conditioned taste aversion. Neurobiol Learn Mem 130, 7–16. [DOI] [PubMed] [Google Scholar]

[R125] Rosenberg T, Elkobi A, Rosenblum K, 2016b. mAChR-dependent decrease in proteasome activity in the gustatory cortex is necessary for novel taste learning. Neurobiol Learn Mem 135, 115–124. [DOI] [PubMed] [Google Scholar]

[R126] Sadanandom A, Bailey M, Ewan R, Lee J, Nelis S, 2012. The ubiquitin-proteasome system: central modifier of plant signalling. New Phytol 196, 13–28. [DOI] [PubMed] [Google Scholar]

[R127] Sadowski M, Suryadinata R, Tan AR, Roesley SN, Sarcevic B, 2012. Protein monoubiquitination and polyubiquitination generate structural diversity to control distinct biological processes. IUBMB Life 64, 136–142. [DOI] [PubMed] [Google Scholar]

[R128] Schafe GE, Nadel NV, Sullivan GM, Harris A, LeDoux JE, 1999. Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn Mem 6, 97–110. [PMC free article] [PubMed] [Google Scholar]

[R129] Scudder SL, Gonzales FR, Howell KK, Stein IS, Dozier LE, Anagnostaras SG, Zito K, Patrick GN, 2021. Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning. eNeuro 8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R130] Shang F, Taylor A, 2011. Ubiquitin-proteasome pathway and cellular responses to oxidative stress. Free Radic Biol Med 51, 5–16. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R131] Singh M, Denny H, Smith C, Granados J, Renden R, 2018. Presynaptic loss of dynaminrelated protein 1 impairs synaptic vesicle release and recycling at the mouse calyx of Held. J Physiol 596, 6263–6287. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R132] Speese SD, Trotta N, Rodesch CK, Aravamudan B, Broadie K, 2003. The ubiquitin proteasome system acutely regulates presynaptic protein turnover and synaptic efficacy. Curr Biol 13, 899–910. [DOI] [PubMed] [Google Scholar]

[R133] Spit M, Rieser E, Walczak H, 2019. Linear ubiquitination at a glance. J Cell Sci 132. [DOI] [PubMed] [Google Scholar]

[R134] Strang J, Volkow ND, Degenhardt L, Hickman M, Johnson K, Koob GF, Marshall BDL, Tyndall M, Walsh SL, 2020. Opioid use disorder. Nat Rev Dis Primers 6, 3. [DOI] [PubMed] [Google Scholar]

[R135] Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S, 2004. Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24, 4787–4795. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R136] Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM, 2011. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810–823. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R137] Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K, 2009. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11, 123–132. [DOI] [PubMed] [Google Scholar]

[R138] Toma-Fukai S, Shimizu T, 2021. Structural Diversity of Ubiquitin E3 Ligase. Molecules 26. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R139] Vann SD, Aggleton JP, Maguire EA, 2009. What does the retrosplenial cortex do? Nat Rev Neurosci 10, 792–802. [DOI] [PubMed] [Google Scholar]

[R140] Wang L, Rodriguiz RM, Wetsel WC, Sheng H, Zhao S, Liu X, Paschen W, Yang W, 2014. Neuron-specific Sumo1–3 knockdown in mice impairs episodic and fear memories. J Psychiatry Neurosci 39, 259–266. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R141] Werner CT, Milovanovic M, Christian DT, Loweth JA, Wolf ME, 2015. Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration. Neuropsychopharmacology 40, 3006–3014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R142] Werner CT, Mitra S, Martin JA, Stewart AF, Lepack AE, Ramakrishnan A, Gobira PH, Wang ZJ, Neve RL, Gancarz AM, Shen L, Maze I, Dietz DM, 2019. Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving. Sci Adv 5, eaay0351. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R143] Werner CT, Viswanathan R, Martin JA, Gobira PH, Mitra S, Thomas SA, Wang ZJ, Liu JF, Stewart AF, Neve RL, Li JX, Gancarz AM, Dietz DM, 2018. E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking. Biol Psychiatry 84, 881–892. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R144] Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ, 1996. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2, 699–703. [DOI] [PubMed] [Google Scholar]

[R145] Yang L, Wang S, Lim G, Sung B, Zeng Q, Mao J, 2008a. Inhibition of the ubiquitin-proteasome activity prevents glutamate transporter degradation and morphine tolerance. Pain 140, 472–478. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R146] Yang L, Wang S, Sung B, Lim G, Mao J, 2008b. Morphine induces ubiquitin-proteasome activity and glutamate transporter degradation. J Biol Chem 283, 21703–21713. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R147] Zhang Z, Cao M, Chang CW, Wang C, Shi X, Zhan X, Birnbaum SG, Bezprozvanny I, Huber KM, Wu JI, 2016. Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling. Mol Cell Biol 36, 70–83. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R148] Zou Z, Wang H, d’Oleire Uquillas F, Wang X, Ding J, Chen H, 2017. Definition of Substance and Non-substance Addiction. Adv Exp Med Biol 1010, 21–41. [DOI] [PubMed] [Google Scholar]

PERMALINK

The ubiquitin-proteasome system and learning-dependent synaptic plasticity - a 10 year update

Morgan B Patrick

Nour Omar

Craig T Werner

Swarup Mitra

Timothy J Jarome

Abstract

1. Introduction

2. Ubiquitin-Proteasome System

2.1. Proteasome Structure

Figure 1. The ubiquitination process.

2.2. Ubiquitination Process

Figure 2. The 26S proteasome complex.

3. The ubiquitin-proteasome system and activity-dependent synaptic plasticity

4. Protein Degradation and Memory: The importance of sex as a biological variable

4.1. Memory Consolidation

4.1.1. Inhibition of protein degradation

4.1.2. Regulation of protein degradation

4.1.3. Temporal dynamics of protein degradation following learning

4.1.4. Subcellular localization of protein degradation following learning

4.1.5. Protein targets of protein degradation during memory consolidation

4.2. Memory Reconsolidation

4.2.1. Inhibition of protein degradation

4.2.2. Regulation of protein degradation

4.2.3. Temporal dynamics of protein degradation following retrieval

4.2.4. Subcellular localization of protein degradation after retrieval

4.2.5. Targets of protein degradation during reconsolidation

4.3. Protein degradation and sex as a biological variable

5. Degradation-independent ubiquitin signaling and memory

5.1. Monoubiquitin

5.2: Linear Polyubiquitination

5.3. K63 Polyubiquitination

5.4. SUMOylation

5.5. Degradation-independent ubiquitin signaling and sex as a biological variable

6. The role of RPT6 in memory formation

7. The ubiquitin-proteasome system and memory formation - updating the models

Figure 3. Cellular model of ubiquitin-proteasome activity during memory consolidation in males.

Figure 4. Cellular model of ubiquitin-proteasome activity during memory consolidation in females.

8. The ubiquitin-proteasome system and substance use disorder

8.1. UPS neuroadaptations underlying SUD

8.1.1. Opioids

8.1.2. Methamphetamine

8.1.3. Cocaine

8.1.4. Alcohol

9. Conclusions and future directions

Highlights.

Acknowledgements

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases