Neuroimmune regulation of the prefrontal cortex tetrapartite synapse

Abstract

The prefrontal cortex (PFC) is an essential driver of cognitive, affective, and motivational behavior. There is clear evidence that the neuroimmune system directly influences PFC synapses, in addition to its role as the first line of defense against toxins and pathogens. In this review, we first describe the core structures that form the tetrapartite PFC synapse, focusing on the signaling microdomain created by astrocytic cradling of the synapse as well as the emerging role of the extracellular matrix in synaptic organization and plasticity. Neuroimmune signals (e. g. pro-inflammatory interleukin 1β) can impact the function of each core structure within the tetrapartite synapse, as well as promote intra-synaptic crosstalk, and we will provide an overview of recent advances in this field. Finally, evidence from post mortem human brain tissue and preclinical studies indicate that inflammation may be a key contributor to PFC dysfunction. Therefore, we conclude with a mechanistic discussion of neuroimmune-mediated maladaptive plasticity in neuropsychiatric disorders, with a focus on alcohol use disorder (AUD). Growing recognition of the neuroimmune system’s role as a critical regulator of the PFC tetrapartite synapse provides strong support for targeting the neuroimmune system to develop new pharmacotherapeutics.

1. The neuroimmune system influences PFC function during health and disease

The prefrontal cortex (PFC) is essential for many cognitive, emotional and motivational processes, with its dorsolateral subdivision (dlPFC) involved in general executive control while the ventromedial PFC (vmPFC) mediates social, cognitive, and affective functions (Badre and Wagner, 2004; Hiser and Koenigs, 2018). As a result, PFC dysfunction is implicated in several neuropsychiatric diseases, including alcohol use disorder (AUD) and other substance use disorders (Soleimani et al., 2024). Converging evidence from post mortem human brain tissue highlights inflammation as a likely contributor to the pathophysiology of neuropsychiatric diseases, suggesting long-term neuroimmune-induced changes in PFC neuronal activity (Crews et al., 2017). There is also growing preclinical evidence that the neuroimmune system regulates healthy (i.e., basal) PFC function to allow for complex behavior (Kopec et al., 2019). As a result, determining how neuroimmune signals influence synaptic transmission and promote maladaptive synaptic plasticity during disease are both priorities. In this review, we describe the core structures that form the PFC synapse, with a focus on the signaling microdomain created by astrocytic cradling of the synapse, as well as the emerging role of the extracellular matrix (ECM) in synaptic organization and plasticity. We also discuss recent advances in our understanding of how neuroimmune signals regulate each of these structures, highlight neuroimmune mechanisms of crosstalk, and consider the role of neuroimmune-mediated maladaptive plasticity in neuropsychiatric disorders. Specifically, chronic low-grade neuroinflammation is implicated in alcohol use disorder (AUD) and other neuropsychiatric disorders with high comorbidity, such as major depressive disorder, anxiety disorders, and schizophrenia. Tetrapartite synapse dysfunction, including neuroimmune signaling alterations, in individuals with AUD can contribute to both alcohol withdrawal symptoms and the development of cognitive dysfunction. Additionally, chronic alcohol use induces changes in synaptic function and neuroimmune signaling that shift brain regions like the prefrontal cortex toward a hyperexcitable state, which may increase the risk of developing comorbid disorders. This understanding has prompted drug discovery efforts targeting the neuroimmune system to restore synaptic balance with which to treat AUD and related disorders.

2. The tetrapartite synapse

The human dl/vmPFC and rodent medial PFC (mPFC) have similar laminar cytoarchitecture and functional circuitry to support higher order processing (Uylings et al., 2003). In the rodent, the prelimbic mPFC uses contextual information to parse conflicting motivational drives and develop goal-directed response strategies (e.g. expression of conditioned fear responses or drug-seeking behavior); the infralimbic mPFC facilitates active avoidance and exerts inhibitory control on behavior (e.g. extinction of conditioned fear responses or suppression of drug-seeking behavior); and the anterior cingulate cortex plays an important role in processing social information to guide decision making (Apps et al., 2016; Capuzzo and Floresco, 2020). Within the dl/vmPFC and mPFC, excitatory pyramidal neurons are arranged into layers that receive distinct local and long-range glutamatergic inputs, as well as inhibition by several classes of γ-aminobutyric acid (GABA) interneurons (Anastasiades and Carter, 2021; Fish and Joffe, 2022).

2.1. Pre/postsynaptic terminal

There are key structural differences between mPFC excitatory and inhibitory synapses. Specifically, glutamatergic synapses include a larger postsynaptic scaffolding on the dendritic spine (Harris and Weinberg, 2012), while GABAergic synapses have symmetrical pre- and postsynaptic terminals, with the latter located directly on the dendritic shaft, cell soma or axon initial segment, as well as on dendritic spines (Chiu et al., 2013; Harris and Weinberg, 2012). mPFC GABAergic neurons also show a large amount of neurochemical and functional diversity, which allows for efficient gating of neuronal activity, the dynamic matching of increased glutamatergic excitatory drive with greater inhibitory input (i.e. maintaining synaptic excitation and inhibition (E/I) balance critical for PFC processing and cognitive performance (Tran et al., 2019)), and the shaping of synaptic plasticity within the cortical microcircuit (Kubota et al., 2016; Riedemann, 2019). It is important to note that most studies of the tetrapartite synapse have focused on the glutamatergic system; however, recent findings specific to GABAergic synapses will be highlighted wherever possible.

2.2. Astrocytes

Astrocytes comprise ~20–40% of all cells in the central nervous system (Khakh and Sofroniew, 2015). They play key roles in multiple physiological processes critical for brain development and health, including synaptogenesis, synaptic pruning and regulating synaptic transmission (Sofroniew and Vinters, 2010).

2.2.1. Astrocyte-synaptic communication

A single human cortical astrocyte associates with approximately two million synapses, while a mouse cortical astrocyte contacts about one hundred thousand synapses (Bushong et al., 2002; Oberheim et al., 2009). While each astrocyte has a distinct non-overlapping territory (Bushong et al., 2002; Stork et al., 2014), the contact points between astrocytes and synapses allow for complex bidirectional signaling that can induce astrocytic calcium waves, regulate local synaptic activity, and synchronize the wider neural network (Fig. 1A). Specifically, perisynaptic astrocytic processes express neurotransmitter receptors that allow them to activate intracellular cascades and generate dynamic calcium transients (Bazargani and Attwell, 2016). One key example of this involves neuronally-released glutamate binding to the astrocytic metabotropic glutamate receptor 5 (mGluR5), a G_q protein-coupled receptor (G_qPCR), whose activation triggers calcium release from the endoplasmic reticulum (Ross et al., 2005). Similarly, GABA released from interneurons activates astrocytic GABA_BR to increase intracellular calcium (Gould et al., 2014). Integration of neurotransmitter-induced calcium transients within a single or few perisynaptic processes may be large enough to trigger a calcium wave that activates the astrocyte, and propagates to other astrocytes via gap junctions (Bazargani and Attwell, 2016).

Fig. 1. Neuroimmune regulation of the PFC glutamatergic tetrapartite synapse.

A. The tetrapartite synapse is a signaling microdomain where astrocytic leaflets cradle pre- and postsynaptic terminals that are surrounded by an extracellular matrix. Each of these four core structures play a key role in glutamate transmission. B. Neuroimmune signals, like interleukin 1β (IL-1β), facilitate intra-synaptic crosstalk. C. Pro-inflammatory A1 astrocytes can be neurotoxic, and generally reduce glutamatergic signaling via both pre- and postsynaptic mechanisms. D. A2 astrocytes more effectively remove excess glutamate from the synaptic cleft to potentially protect neurons from excitotoxicity. Abbreviations: A1, proinflammatory reactive astrocyte; A2, neuroprotective reactive astrocyte; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; Best-1, bestrophin 1; CamKII, calmodulin-dependent kinase II; GLAST, glutamate aspartate transporter; GLT-1, glutamate transporter 1; IL-1β, interleukin 1 beta; IL-1R1, interleukin 1 receptor type 1; IP₃R, inositol 1,4,5-triphosphate receptor; mGluR, metabotropic glutamate receptor; MMP-9, matrix metalloproteinase 9; NMDAR, N-methyl-D-aspartate receptor; PSD-95, postsynaptic density protein 95; SNARE, soluble n-ethylmaleimide-sensitive factor attachment proteins receptor; vGLUT, vesicular glutamate transporter. Created in BioRender.

Calcium waves often induce the astrocytic release of gliotransmitters into the synapse where they bind pre- and postsynaptic terminal receptors (Khakh and McCarthy, 2015). While several gliotransmitters have been identified, including adenosine/adenosine triphosphate (Lezmy et al., 2021), glycine (Nimitvilai-Roberts et al., 2021), and D-serine (Kang et al., 2013), most studies have focused on glutamate (Bezzi et al., 1998; de Ceglia et al., 2023; Jourdain et al., 2007; Parpura et al., 1994) and GABA (Lee et al., 2010; Yoon et al., 2011). Once released, these gliotransmitters can produce either fast immediate or slow long-reaching modulation of synaptic and neuronal activity.

2.2.1.1. Glutamate.

Astrocytic production of glutamate has not been reported; instead, astrocytic glutamate is sourced via uptake from the synaptic cleft by glutamate transporters (see section 2.2.1.3 for more details; Fig. 1A) (Bushong et al., 2002; Pajarillo et al., 2019). Several mechanisms of astrocytic glutamate release have been identified, many of which involve calcium-mediated exocytosis (Mahmoud et al., 2019). Most commonly, astrocytes possess similar vesicular release machinery as neurons, including small intracellular vesicles that express vesicular glutamate transporters 1–3 (vGLUT 1–3) (Bezzi et al., 2004; de Ceglia et al., 2023; Fremeau et al., 2002), as well as vesicular and plasma membrane soluble n-ethylmaleimide-sensitive factor attachment proteins receptors (SNARE) and synaptotagmin (Bezzi et al., 2004; de Ceglia et al., 2023; Hepp et al., 1999; Zhang et al., 2004). Slow astrocytic glutamate release can also occur following stimulation of the calcium-activated anion channel bestrophin 1 (Harinstein et al., 2012). Calcium-independent pathways have also been identified, including astrocytic P2X purinoceptor 7 (Duan et al., 2003), cystine/glutamate antiporters (Baker et al., 2002), and the potassium channel subfamily K member 2 (Woo et al., 2012).

Glutamate released from astrocytes can bind synaptic terminal receptors to regulate their neurotransmission (Mahmoud et al., 2019). Specifically, astrocytic release of glutamate can activate presynaptic mGluR1 to enhance neuronal glutamate release (Jourdain et al., 2007; Perea and Araque, 2007). Astrocytic glutamate activation of presynaptic mGluR2/3 can also decrease the probability of glutamate release from presynaptic terminals (Andersson et al., 2007). Furthermore, glutamate release from astrocytes can potentiate neuronal inhibition. In this case, neuronal GABA binds to astrocytic GABA_BR causing a rise in intracellular calcium levels that stimulates astrocytic glutamate release (Mahmoud et al., 2019). This astrocytic glutamate can then bind to postsynaptic N-methyl-D-aspartate receptors (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) which triggers action potential-dependent GABA release from nearby interneurons (Kang et al., 1998).

2.2.1.2. GABA.

Astrocytic GABA production, accumulation and release can occur via multiple mechanisms. A large amount of astrocytic GABA is taken up from the synaptic cleft by the GABA transporter (GAT) (Losi et al., 2014); however, GABA is also produced in astrocytes from the precursors glutamate and putrescine (Kwak et al., 2020; Yoon et al., 2014). In the cortex, GAT-3 is predominantly found on cortical astrocyte processes in close proximity to synapses (Melone et al., 2015), and has been shown to regulate tonic GABA release (Kinney, 2005). GAT-3-mediated GABA release from astrocytes can also suppress GABAergic neurotransmission via a presynaptic GABA_BR receptor-mediated mechanism (Kirmse and Kirischuk, 2006). Importantly, GABA release has also been observed in human astrocytic cultures (Lee et al., 2011), suggesting that its signaling may play a critical role in modulating cortical network activity across species.

2.2.1.3. Astrocytes regulate pre- and postsynaptic terminal activity via neurotransmitter reuptake.

Astrocytes can also regulate neurotransmission by acting as conduit for glutamate and GABA recycling back to the presynaptic terminal (Fig. 1A). Specifically, when glutamate is released from the presynaptic terminal, astrocytes remove the excess via the glutamate transporter 1 (GLT-1 in rodents or EAAT2 in humans) and glutamate-aspartate transporter (GLAST in rodents or EAAT1 in humans) to prevent its synaptic accumulation and subsequent excitotoxicity (Pajarillo et al., 2019). Astrocytic glutamate is then processed into glutamine (Anlauf and Derouiche, 2013). Likewise, GABA is transported into astrocytes predominantly by GAT-3 (Conti et al., 2004), and shuttled back as glutamine into presynaptic terminals via solute carrier-type transporters 38A1 and 38A2 (Bak et al., 2006; Bhutia and Ganapathy, 2016).

Recent evidence indicates astrocytes can have a large influence over synaptic transmission and thereby shift the E/I balance. For example, in adult male mice, chemogenetic astrocyte stimulation in the dorsomedial PFC depolarizes neurons by increasing local glutamate release and decreasing postsynaptic GABA_AR function (Noh et al., 2023). Additionally, acute PFC GLT-1 inhibition prevented reductions in depolarization-evoked glutamate release following chronic social defeat stress (Kosuge et al., 2024). While few studies have examined the consequences of mPFC astrocytic regulation of synapses on behavior, dominant male mice show greater dorsomedial PFC astrocytic calcium activity during a social interaction tube test compared to their submissive counterparts (Noh et al., 2023). Another study showed that viral inhibition of calcium activity in mPFC astrocytes reduced alcohol intake and preference in male mice (Erickson et al., 2021). Given the complexity of bidirectional astrocytic-synaptic signaling, much more work is needed to disentangle the role of astrocytes in regulating basal mPFC function, as well as in the pathophysiology of disease.

2.3. Extracellular matrix

The brain’s extracellular space is divided into functional microdomains determined by the ECM macromolecular composition (Dankovich and Rizzoli, 2022). Perisynaptic ECM loosely wraps around individual synapses, while more specialized perineuronal net ECM (PNN) tightly surrounds the soma and proximal dendrites of inhibitory neurons in select brain regions including the prefrontal cortex (Dankovich and Rizzoli, 2022; Ueno et al., 2017). In both cases, the ECM mesh-like structure contains chondroitin sulfate proteoglycans (CSPG), glycoproteins, and glycosaminoglycans (usually hyaluronan). These ECM molecules are secreted from astrocytes and neurons and cross-linked together, with some also directly interacting with neuronal/glial transmembrane proteins. In particular, hyaluronan tethers the ECM directly to neurons and astrocytes by binding CD44 or other transmembrane cell adhesion proteins. Therefore, ECM degradation by extracellular proteases (e.g. matrix metalloproteinases, MMP) is necessary for synaptic remodeling, synaptogenesis, and the perisynaptic invasion of microglial or astrocytic processes. These proteases, which are secreted by neurons and astrocytes, can also influence neuronal and astrocytic activity by cleaving molecular signals to either initiate or terminate intracellular cascades (Dankovich and Rizzoli, 2022; Niculescu et al., 2018).

2.3.1. Perisynaptic ECM

Several ECM sites of presynaptic regulation have been identified (Fig. 1A). For example, in the anterior cingulate mPFC, the loss of glycoprotein laminins that interact with β1-containing integrin receptors led to presynaptic actin dysregulation and increased probability of glutamate release, though it appeared to also cause postsynaptic spine remodeling (Li et al., 2021). Laminin/β1 integrin signaling likewise reduced the mobilization of reserve pool vesicles in the hippocampus (Huang et al., 2006). In contrast, a second ECM glycoprotein, reelin, increased hippocampal neurotransmitter release from reserve pool vesicles through a presynaptic calcium pathway (Bal et al., 2013).

The perisynaptic ECM also contributes to postsynaptic remodeling. For example, hippocampal post-synapse maturation requires a switch to NR2B-containing NMDAR that involves reelin and integrin-binding ECM molecules (Campo et al., 2009; Schweitzer et al., 2017; Shi and Ethell, 2006). An actin-associated pathway also mediates the effects of reduced laminin/β1 integrin signaling to increase synaptic AMPAR and NMDAR in the anterior cingulate mPFC (Li et al., 2021), while studies that disrupt the ECM report increased extrasynaptic diffusion of AMPAR (Frischknecht et al., 2009). Additionally, MMP-9 activates an integrin β1-dependent pathway to endogenously increase NMDAR surface expression without disrupting the surrounding ECM structure (Michaluk et al., 2009), while MMP-3 inhibition prevents the postsynaptic entrapment of GABA_AR during long-term potentiation (LTP) at inhibitory synapses (Wiera et al., 2017). Critically, many studies only examine one or two specific aspects of ECM-induced synaptic regulation making it difficult to understand the broader functional implications. One more comprehensive study found that hippocampal enzymatic ECM degradation increased glutamate currents and the AMPAR/NMDAR ratio but also reduced pyramidal neuron excitability to suppress LTP, suggesting that the observed postsynaptic plasticity may result from new synapse formation and a compensatory decrease in network activity to prevent overexcitation (Dembitskaya et al., 2021). Maintaining E/I balance is also a key feature of ECM-induced GABAergic plasticity, since reductions in inhibitory synapse density were compensated for by decreased expression of presynaptic GABA_B autoreceptors (Dzyubenko et al., 2021).

Finally, the perisynaptic ECM can mediate synaptic signaling efficacy and extrasynaptic spillover by guiding soluble factors like glutamate and GABA across the synaptic cleft (Xu et al., 2022). In particular, the CSPG brevican is highly expressed within the perisynaptic space, and its knockdown in the calyx of Held reduced the extracellular space between opposing pre- and postsynaptic membranes to alter signal transmission (Blosa et al., 2015). Interestingly, brevican has also been identified as a key regulator of cortical circuits (Favuzzi et al., 2017). Similar perisynaptic ECM properties are also thought to facilitate astrocytic-neuronal bidirectional crosstalk, as well as long-distance hormone, growth factor and neuroimmune signaling (Xu et al., 2022; Zamecnik et al., 2012).

2.3.2. Perineuronal net ECM

Perineuronal nets (PNN) are a condensed form of ECM that envelop the soma and proximal dendrites of parvalbumin-expressing inhibitory neurons (Baker et al., 2017; Brückner et al., 2004; Ueno et al., 2017; Van den Oever et al., 2010). They appear during the final stages of cortical maturation, and their accumulation is thought to induce closure of the juvenile critical period (Willis et al., 2022). PNN can aggregate directly on neurons due to their inclusion of letican CSPG (aggrecan, versican, neurocan and brevican), glycoprotein tenascin-R, and link proteins, in addition to the typical ECM backbone (Carulli and Verhaagen, 2021; Ueno et al., 2017).

As a result of these rigid molecular interactions, axons must perforate the PNN in order to form synapses with parvalbumin interneurons (Sigal et al., 2019). This confers PNN with the ability to stabilize existing synapses, thereby maintaining the local E/I balance. Recent studies using mice deficient in brevican, neurocan, tenascin-C and tenascin-R reported fewer cortical and hippocampal PNN, as well as structural disruption of the remaining PNN, all of which tipped the E/I balance towards excitation and increased network activity (Gottschling et al., 2019; Mueller-Buehl et al., 2022). Interestingly, ~70% of the perforating synapses on PNN-wrapped cortical interneurons also include astrocytic processes that express GLT-1, GAT-1, and GAT-3 (Tewari et al., 2023). Viral depletion of aggrecan disrupted astrocytic glutamate clearance from the synapse, instead causing it to accumulate and spill over into the extrasynaptic space where it overactivates NMDAR to produce excitotoxicity (Parsons and Raymond, 2014; Tewari et al., 2023). PNN also protect against E/I shifts by acting as a molecular “brake” at several junctures of synaptic plasticity (Dick et al., 2013; Mohan et al., 2018; Sullivan et al., 2018). Thus, even though PNN represent less than 2% of all brain ECM, they play an outsized role in regulating cortical activity (Carulli and Verhaagen, 2021).

Several studies report that behavioral learning and memory during adulthood are often enhanced by targeted PNN degradation. For example, mPFC CSPG aggrecan knockdown reduced extinction-induced freezing behavior during retrieval, suggesting persistence of the extinction memory (Lavertu-Jolin et al., 2023). Likewise, enzymatic digestion of mPFC PNN improved rat performance in a spatial working memory task that required higher cognitive load (Anderson et al., 2020). Interestingly, adolescent alcohol exposure increased PNN in the anterior insula cortex of adult rats, which mediated impairments in behavioral flexibility (Sullivan et al., 2024). Previous work has identified a similar increase in rodent mPFC PNN (Dannenhoffer et al., 2022). PNN density and CSPG staining were also increased in the hippocampus of adult male rhesus monkeys that were allowed to freely self-administer alcohol for 1 year (Valeri et al., 2024). Finally, post mortem analyses of human brain tissue from the hippocampus of individuals with substance use disorder showed increased PNN density, accompanied by less Mmp9, increased Chsy1 and Vamp2 gene expression, all of which would support synaptic stabilization (Valeri et al., 2024). This is in contrast to the effects of alcohol on perisynaptic and neurovascular ECM; ECM molecules were down-regulated and MMP-9 proteolytic activity was enhanced in human dlPFC tissue from individuals with AUD (Rubio-Araiz et al., 2017). Overall, these varied results suggest a duality in function, where the synaptic and behavioral effects can greatly differ based on the specific type of ECM involved.

3. Neuroimmune regulation of the tetrapartite synapse

The central nervous system (CNS) was traditionally thought to be immune-privileged; it is enveloped by a semi-permeable blood brain barrier that restricts transfer from the periphery to the brain parenchyma of larger molecules and cells, including pathogens and toxins, immune signals such as cytokines and chemokines, and immune cells like macrophages and leukocytes (Carlson et al., 2023; Liberman et al., 2018). While there is now clear evidence of bidirectional communication between the peripheral and central immune systems, the CNS innate immune system still acts as the first line of defense against toxins and pathogens, phagocytoses debris and dead cells, and promotes healing after tissue injury. Specifically, microglial cells sense pathogen or danger-associated molecular patterns and rapidly release pro-inflammatory cytokines and chemokines (Carlson et al., 2023). This leads to secondary activation of astrocytes which also release inflammatory signals, allowing neuroinflammatory responses to persist well beyond the initial threat (Liberman et al., 2018). Resolution of these responses, as well as repair and cell survival mechanisms, are mediated by a subset of astrocytes and microglia that release anti-inflammatory cytokines and neurotrophic factors. Interestingly, after an acute challenge (such as alcohol intoxication, bacterial infection, or injury) the neuroimmune system may return to a primed state, where it is more susceptible to future insults (Carlson et al., 2023). Regardless, as a whole, acute neuroimmune responses are considered neuroprotective mechanisms that limit tissue damage and support recovery. In contrast, chronic neuroimmune challenges or neuroinflammatory responses that do not resolve appropriately can cause long-term loss of synapses and neurons (Carlson et al., 2023; Liberman et al., 2018). There may also be transient failures at the blood brain barrier that allow pathogens and toxins, as well as peripheral immune signals and cells, to enter the brain parenchyma. All of these persistent negative outcomes have been observed in the brains of individuals with neuropsychiatric disorders, such as AUD, suggesting that chronic neuroinflammation may play a role in disease pathophysiology (Crews et al., 2017; Kyzar and Pandey, 2015; Nunes et al., 2019; Vore and Deak, 2022). Finally, it is important to note that low levels of these same pro- and anti-inflammatory signals have also been detected in the healthy brain, and recent studies report that they can modulate basal synaptic activity to drive complex behaviors (Kopec et al., 2019). It is therefore important to consider both the levels of cytokines/chemokines present and the overall neuroimmunological state of the brain when discussing the influence of neuroimmune signals on each component of the synaptic structure.

3.1. Neuroimmune signaling at the pre-/postsynaptic terminal

Several cytokines regulate synaptic transmission, though their specific mechanisms of action are not always well understood. One of the most studied cytokines, in this regard, is interleukin-1 beta (IL-1β), which can be released “on-demand” from microglia, astrocytes and neurons immediately after being cleaved into its active form by caspase-1 (Fig. 1B) (Nemeth and Quan, 2021). Basal/physiological levels of extracellular IL-1β are generally low (0–65 pg/mL) (Folkersma et al., 2008; Gano et al., 2019; Vasicek et al., 2013), but can oscillate with circadian rhythms and impact behaviors like sleep, depression and memory (Depino et al., 2004; Ingiosi et al., 2015; Li et al., 2024; Taishi et al., 1997). Of note, one technical limitation of these types of microdialysis studies is that the dialysate concentration is only a fraction (often 2–3%) of the actual extracellular fluid (Folkersma et al., 2008; Vasicek et al., 2013), suggesting that in vivo basal levels of IL-1β may be significantly higher than reported. Extracellular IL-1β rapidly rises to pathological levels in response to acute sickness or injury (Folkersma et al., 2008; Kamm et al., 2006). Upon binding its cognate receptor interleukin-1 receptor type 1 (IL-1R1) on neurons, astrocytes and endothelial cells, IL-1β drives several pathological processes by activating the myeloid differentiation primary response 88/p38 mitogen-activated protein kinase (MyD88/p38 MAPK) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) cascades to induce a large number of other proinflammatory cytokines (Nemeth and Quan, 2021). Very high concentrations of IL-1β, often resulting from direct tissue injury, trigger excitotoxicity and apoptotic neuronal death (Nemeth and Quan, 2021). In contrast, IL-1 signaling can also promote cellular growth, survival and repair through its recruitment of downstream effectors such as phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) (Davis et al., 2006).

IL-1 signaling has multiple sites of action at the synaptic terminal, though its specific effects vary based on the brain region and cell-type, concentration and duration of IL-1β exposure, as well as the overall tissue health (Nemeth and Quan, 2021; Pinteaux et al., 2009). Studies using direct application of IL-1β or a IL-1R1 knockout mouse revealed a role for the IL-1 system in promoting terminal pruning via both pre- and postsynaptic mechanisms in the hippocampus (Avdic et al., 2015; Gardoni et al., 2011; Mishra et al., 2012). At the postsynaptic terminal, IL-1 signaling generally enhanced GABA_AR and NMDAR expression and activity, but decreased AMPAR expression across multiple brain regions including the hippocampus, central amygdala and cortex in rodents and non-human primates (Bajo et al., 2015; Patel et al., 2022; Taoro-Gonzalez et al., 2018; Viviani et al., 2003; Wang et al., 2012). Most of these effects are thought to be mediated via intracellular signaling, but interestingly, IL-1β appears to directly interact with NR2B-containing NMDAR to enhance their postsynaptic calcium flux (Huang et al., 2011). The presynaptic effects of IL-1β on neurotransmitter release are more mixed, with acute IL-1β decreasing hippocampal glutamate release (Vereker et al., 2000; Yang et al., 2005), increasing hypothalamic and hippocampal GABA release (Tabarean et al., 2006; Zhu et al., 2006), and having dual effects on GABA release in the male rodent and non-human primate central amygdala (Bajo et al., 2019; Bajo et al., 2015; Bajo et al., 2015; Patel et al., 2022, 2019). Interestingly, we found under basal conditions that IL-1β recruited the neuroprotective PI3K/Akt pathway to decrease GABA release onto prelimbic mPFC layer 2/3 pyramidal neurons in male mice (Varodayan et al., 2023), but not females (Liss et al., 2024). Of note, IL-1-induced neuroprotection may also occur indirectly via astrocytes; IL-1β upregulated astrocytic production of nerve growth factor and transforming growth factor β (TGF-β) (da Cunha et al., 1993; Jauneau et al., 2006), as well as increased glutathione release from cortical astrocytes via a non-p38 MAPK pathway, to reduce oxidative stress injury (He et al., 2015).

Interestingly, IL-1β levels are elevated in neuropsychiatric diseases that are thought to involve chronic low-grade activation of the neuroimmune system, including AUD (Coleman et al., 2018; Crews and Vetreno, 2014). Specifically, chronic alcohol exposure increased IL-1β in the rodent and non-human primate mPFC/PFC (Varodayan et al., 2023; Walter et al., 2020; Warden et al., 2020). In alcohol-exposed male mice, this was accompanied by a mechanistic switch such that IL-1β now recruited pro-inflammatory MyD88 to increase mPFC GABAergic transmission (vs. its engagement of PI3K/Akt to decrease GABA release in control mice) (Varodayan et al., 2023), supporting the idea that overall tissue health is critical factor in how neuroimmune signaling impacts synaptic activity.

Elevated levels of IL-1β also signal more broadly across the different core structures of the tetrapartite synapse to promote synaptic loss and neuronal apoptosis (Fig. 1B). Specifically, IL-1β reduced astrocytic clearance of glutamate in the synaptic cleft by inhibiting the cystine/glutamate transporter (Jackman et al., 2010); it also increased astrocytic release of free radicals (Thornton et al., 2006). Additionally, IL-1 signaling can induce neurotoxicity by down- or upregulating astrocytic release of enzymes that protect (tissue inhibitor of metalloproteinase-1) or degrade (MMP-9) the extracellular matrix, respectively (Fields et al., 2013; Wilczynska et al., 2006). Finally, astrocytic adhesion to the ECM was found to be essential for IL-1β to induce a reactive phenotype in astrocytes (Summers et al., 2010). Besides IL-1β, there is clear evidence that several other neuroimmune signals (e.g. tumor necrosis factor α, TNF-α; IL-13; IL-6) can also regulate core structures within the tetrapartite synapse, with each cytokine potentially supporting multiple structural and functional outcomes (Zipp et al., 2023). As a result, future studies are needed to characterize how a broader neuroimmune challenge shapes synaptic plasticity, particularly in the context of complex disease states such as AUD.

3.2. Neuroimmune signaling via astrocytic processes

The neuroimmune system regulates astrocyte function in basal conditions, as well as during threat, though the specific signals will vary based on the tissue state (Hasel et al., 2021). Astrocytes express a variety of receptors for neuroimmune signaling molecules, including pattern recognition receptors such as toll-like receptors (TLR) which responds to a variety of insults, including alcohol exposure, injury, and illness (Li et al., 2021). Microglial signaling via these neuroimmune receptors can also activate astrocytes (i.e. astrocytes become “reactive”; see section 3.2.1 for more details), leading to the secretion of either pro- and anti-inflammatory cytokines such as IL-1β, IL-6, and TNF-α as part of the overall neuroinflammatory response to insult (Gao et al., 2013; Park et al., 2019).

3.2.1. Astrocyte reactivity

Astrocyte “reactivity” refers to the rapid changes in morphology, gene expression, and function that astrocytes undergo in response to insult or injury in the brain (Escartin et al., 2021). Specifically, reactive astrocytes display modest morphological changes, including enlargement of their cell bodies and processes, as well as increases in the number and length of their processes. Two types of reactive astrocytes, pro-inflammatory A1 and neuroprotective A2, have been identified based on their responses to LPS treatment (Fig. 1C and D) (Liddelow et al., 2017; Zamanian et al., 2012). While this dichotomy does not reflect the diversity of astrocytic phenotypes (Batiuk et al., 2020; Hasel et al., 2021), recent work has nonetheless revealed important differences between the A1 and A2 states that contribute to our understanding of astrocyte participation in health and disease.

In general, A1 activation allows for a secondary pro-inflammatory response to brain insult or injury; however, A1 astrocytes can also be considered neurotoxic and may exacerbate disease pathologies. A1 astrocytes preferentially express 57 different genes compared to A2 astrocytes, including the most commonly used A1 marker complement protein C3, which is responsible for synaptic pruning (Guo et al., 2020; Zamanian et al., 2012). Their pro-inflammatory phenotype is induced after microglial release of several neuroimmune signals, including IL-1α, TNF-α, and complement component 1q subcomponent (Liddelow et al., 2017). Exposure to TGF-β1 and interferon gamma, two cytokines often released by microglia (Flanders et al., 1998; Kawanokuchi et al., 2006), also altered expression of multiple genes associated with calcium signaling in cultured astrocytes (Hamby et al., 2012), providing further evidence that cytokines promote astrocyte reactivity. A key signaling pathway involved in the induction of A1 astrocyte reactivity is the Janus kinase/signal transducer and activator of transcription 3 pathway. Activation of this pathway increased glial fibrillary acidic protein expression (Hol and Pekny, 2015), a common indicator of astrocyte reactivity, while inhibition of this pathway in astrocytes reduced mRNA levels of pro-inflammatory cytokines such as IL-1β and IL-6, suggesting it is important for inducing A1 astrocyte reactivity (Wang et al., 2012). Pro-inflammatory cytokine release from A1 reactive astrocytes can also be induced through activation of NF-κB, a primary mediator of pro-inflammatory gene production (Lawrence, 2009).

Release of pro-inflammatory cytokines or other neurotoxins, such as nitrous oxide, from A1 reactive astrocytes can cause a loss of dendritic arborization, as well apoptosis of neurons and other cells types like oligodendrocyte precursor cells (Fig. 1C) (Lian et al., 2015; Liddelow et al., 2017). A1 astrocytes also show a reduced capacity for supporting synapse formation and function, which can lead to overall synaptic and dendritic spine loss. Although the underlying mechanisms remain largely unclear, transcriptomic analyses reveal that A1 astrocytes generally display a down-regulation of neuro- and synapto-protective factors (e.g. PI3K/Akt pathway, growth factors like brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor) and an upregulation of the complement cascade (Hong et al., 2016; Lawrence et al., 2023). Expression of these latter genes can cause synapse elimination (Stevens et al., 2007). Finally, A1 astrocytes have increased expression of nitric oxide synthase (Luna-Herrera et al., 2020) and subsequent excitotoxicity (Araki et al., 2020). While little work has directly examined how A1 astrocytes may influence synaptic transmission, a recent study found that they decreased the expression of synaptic proteins in cultured cortical neurons, including PSD-95, calmodulin-dependent kinase II, synaptophysin, and synapsin I (Hong et al., 2020), suggesting that A1 astrocytes may alter synaptic transmission through pre- and post-synaptic remodeling.

In contrast, A2 astrocytes have a neuroprotective phenotype and are activated after brain insult or injury (Zamanian et al., 2012). 150 genes, including the commonly used A2 marker S100 calcium binding protein A10 (S100A10), are preferentially expressed in A2 astrocytes (Guo et al., 2020; Zamanian et al., 2012). Compared to A1 astrocytes, the direct or indirect effects of A2 astrocytes on neurons remain largely understudied. Gene expression profiling of A2 astrocytes revealed that they upregulate many genes associated with neurotrophic and anti-inflammatory factors that are beneficial to neuron health and synaptic repair, including IL-6, IL-10, thrombospondins, and cardiotrophin-like cytokine factor 1 (Zamanian et al., 2012). A2 astrocytes also have increased GLAST expression and glutamate uptake, suggesting that they can more effectively remove excess glutamate from the synaptic cleft to potentially protect neurons from excitotoxicity (Fig. 1D) (Neal et al., 2018). Following injury, astrocytes interact with the ECM to facilitate repair and remodeling by forming a glial scar (Williamson et al., 2021). Multiple lines of evidence suggest it is largely A2 astrocytes that form glial scars, as they secrete signaling molecules involved in glial scar formation such as signal transducer and activator of transcription 3 and TGF-β (He et al., 2020; Schachtrup et al., 2010), along with neurotrophic factors and molecules that inhibit inflammation (He et al., 2020; Schachtrup et al., 2010). However, A1 reactive astrocytes are also involved in glial scar formation, as they secrete cytokines to limit the spread of inflammation (Hensel et al., 2019). Future studies are greatly needed to clarify how A1 and A2 reactive astrocytes participate in synaptic transmission and cortical functions. Additionally, further consideration of astrocyte phenotypes beyond the A1/A2 dichotomy could provide valuable insight into the mechanisms of reactive astrocytes in the context of the neuroimmune system.

3.3. Neuroimmune signaling via the ECM

The ECM is critical for CNS injury and repair processes. Inflammation can cause ECM degradation, and the resulting fragments can serve as danger-associated molecular patterns to activate microglial and astrocytic pattern recognition receptors and trigger neuroimmune responses (Raposo and Schwartz, 2014). For example, in the rodent spinal cord, hyaluronan can act as an immunosuppressant, while its fragmentation induced microglial pro-inflammatory TLR2/4 and NF-κB cascades and promoted IL-1β synthesis, release and maturation (Gaudet and Popovich, 2014). Likewise, MMP-9 activated the pattern recognition receptor known as receptor for advanced glycation endproducts in the mouse anterior cingulate mPFC, leading to NF-κB signaling and cytokine release, as well as oxidative stress (Dwir et al., 2020). In both these cases, the ensuing wave of cytokine release could potentially stimulate astrocytic release of more MMP, which would further degrade the ECM and promote astrogliosis and scar formation (Hayes and Melrose, 2021). Astrocytes within the glial scar may also secrete large amounts of the ECM constituent CSPG, which can create a barrier to prevent axon regeneration and synaptic sprouting into the damaged area.

It is not known whether there are direct neuroimmunological actions of the ECM at synapses. Astrocytic overexpression of MMP-1 increased dendritic complexity, while excessive MMP-9 activity disrupted dendritic spine maturation and impaired LTP (Allen et al., 2016; Magnowska et al., 2016; Wang et al., 2008). Both of these MMPs (as well as others) cleave pro-form cytokines (Chaves Filho et al., 2022), and several of the resulting cytokines, such as TNF-α and IL-1β, have been shown to regulate the E/I balance by altering presynaptic neurotransmitter release, receptor trafficking, and mechanisms of synaptic plasticity (Zipp et al., 2023). At the same time, pro-inflammatory signaling (e.g. IL-1β; IL-33; TGF-β; NF-κB; TNF-α) can stimulate the secretion of new ECM molecules or instruct for their removal to bidirectionally regulate synaptic remodeling in the brain (Hamel et al., 2005; Namba et al., 2022; Nguyen et al., 2020; Vos et al., 2000).

4. Maladaptive plasticity of the tetrapartite synapse in alcohol use disorder and other neuropsychiatric diseases

Chronic low-grade neuroinflammation is associated with synaptic dysfunction in AUD, as well as other neuropsychiatric disorders that have high comorbidity with AUD, like major depressive disorder (MDD), stress and anxiety disorders, and schizophrenia (Becker and Lopez, 2016; Erickson et al., 2019). Individuals with AUD have elevated plasma, brain and cortical levels of cytokines and their receptors (e.g. IL-8, monocyte chemoattractant protein-1, IL-1β, TNF-α, IL-6, TLR2–4, receptor for advanced glycation endproducts) (Crews et al., 2013; He and Crews, 2008; Kazmi et al., 2022; Moura et al., 2022; Vetreno et al., 2013; Zou and Crews, 2012). Indirect evidence from animal models suggests that these pro-inflammatory factors are associated with the physical symptoms and negative affective state that emerge during alcohol withdrawal (Crews et al., 2017), as well as cognitive dysfunction during protracted abstinence (Palmer et al., 2019). Of note, alcohol intoxication increases corticosteroid production (including glucocorticoids), and activates the hypothalamic-pituitary-adrenal axis to indirectly alter neuroimmune function in a dose-dependent manner. Specifically, low glucocorticoid concentrations increase immune responsiveness, whereas high glucocorticoid concentrations are immunosuppressive (Lim et al., 2007). Moreover, pro-inflammatory cytokines, such as IL-1β, can induce glucocorticoid resistance by disrupting both glucocorticoid receptor expression and function (Pace et al., 2007). Therefore, repeated bouts of alcohol intoxication can ultimately cause resistance to the anti-inflammatory effects of high concentrations of glucocorticoids and exacerbate neuroimmune responses (Willey et al., 2012). This aligns with the findings that individuals with AUD who are in early stage withdrawal are more likely to show glucocorticoid resistance, though this normalizes with sustained abstinence (Dunne and Ivers, 2023), and that the glucocorticoid receptor antagonist mifepristone decreased alcohol-cued craving and reduced alcohol consumption in abstinent individuals with AUD (Vendruscolo et al., 2015). While the exact mechanisms underlying how these intertwined signaling pathways contribute to the negative behavioral outcomes of AUD has yet to be fully elucidated, it is believed that the neuroimmune system’s dynamic control of PFC synapses plays a critical role throughout disease progression.

A single episode of binge alcohol consumption can induce a transient anti-inflammatory state during intoxication followed by a proinflammatory period during withdrawal (Afshar et al., 2015). Therefore, in addition to the direct synaptic effects of alcohol exposure to enhance neurotransmitter release, inhibit AMPAR and NMDAR, and potentiate GABA_AR currents (Allan et al., 1991; Siddiqi et al., 2023; Varodayan et al., 2018; Varodayan et al., 2011; Varodayan and Harrison, 2013; Weitlauf and Woodward, 2008; Wirkner et al., 2000), alcohol-induced dynamic changes in cytokine levels (Doremus-Fitzwater et al., 2014) can alter synaptic function within minutes to hours as well as produce long-term adaptations that lead to sustained alterations in network function (McCarthy et al., 2018). For example, a recent study using primary culture of cortical astrocytes found that acute alcohol increased glutamate release via IL-1β/TLR4 signaling (Fig. 2) (Gómez et al., 2024). IL-10 was similarly released from cultured cortical neurons in response to acute alcohol (Suryanarayanan et al., 2016); of note, IL-10 dose-dependently reduced GABA transmission in both cultured cortical neurons as well as DG neurons in the hippocampus (Suryanarayanan et al., 2016), but slightly increased postsynaptic GABA_AR function in infralimbic mPFC pyramidal neurons (Patel et al., 2021).

Fig. 2. Alcohol-induced neuroimmune dysfunction at the tetrapartite synapse.

Chronic alcohol use can shift the PFC toward a hyperexcitable state and increase the risk of developing comorbid neuropsychiatric disorders by (1) increasing IL-1β production and release, (2) directly and indirectly increasing glutamate release, (3) regulating AMPAR, NMDAR and mGluR5 expression and activity, and (4) inhibiting glutamate reuptake by astrocytes. Abbreviations: AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GLAST, glutamate aspartate transporter; IL-1β, interleukin 1 beta; IL-1R1, interleukin 1 receptor type 1; mGluR5, metabotropic glutamate receptor 5; MMP-9, matrix metalloproteinase 9; NMDAR, N-methyl-D-aspartate receptor; TLR4, toll-like receptor 4. Created in BioRender.

Chronic alcohol exposure triggers assembly of the inflammasome NLRP3 complex, which induces caspase-1 production of IL-1β (Fig. 2) (Strowig et al., 2012). In addition to IL-1β′s role as a key regulator of several pro-inflammatory cascades (Nemeth and Quan, 2021), it can also activate a tryptophan metabolic pathway to induce astrocytic glutamate release and prevent astrocytic glutamate reuptake (Miller and Raison, 2016); the ensuing hyperexcitability was associated with impairments in mPFC LTP and working memory (Miller and Raison, 2016). Interestingly, IL-1β′s regulation over prelimbic mPFC GABAergic synapses was also altered by chronic alcohol (Varodayan et al., 2023), while the postsynaptic GABA_AR effect of IL-10 on infralimbic mPFC neurons was blunted (Patel et al., 2021). PFC levels of proteins involved in GABA synthesis and release (glutamic acid decarboxylase (GAD) 1 and 2, and synaptophysin), as well as GABA_AR function (GABRA1) were also decreased by chronic alcohol (Yao et al., 2022), and activation of NF-κB/TNF signaling led to aberrant PFC synaptic pruning (Socodato et al., 2020). Interestingly, adolescent TLR4-deficient mice did not show the typical pattern of alcohol-induced PFC synaptic structural changes or the accompanying cognitive impairment (Montesinos et al., 2015), though there was only a limited role for TLR4 at CeA synapses of alcohol-exposed adult rats (Varodayan et al., 2018). Overall, this preclinical work supports the findings of human imaging studies that report cortical GABA_AR dysfunction in individuals with AUD, as indexed by decreased benzodiazepine site availability (Abi-Dargham et al., 1998; Lingford-Hughes et al., 1998). Additionally, post mortem PFC tissue from individuals with AUD showed increased extracellular glutamate (Freund and Anderson, 1996; Hoffman and Tabakoff, 1994), as well as increased growth factor/cytokine midkine and astrocytic EAAT1 protein expression, perhaps as protection against the hyperglutamatergic state that results from repeated drinking episodes (Flatscher-Bader and Wilce, 2008; Kashem et al., 2019). As such, treatment with endostatin, which is endogenously produced by proteolytic cleavage of ECM collagen XVIII, suppressed NF-κB phosphorylation, recovered prelimbic mPFC alterations in glutamate transmission and LTP, and reduced relapse in alcohol-drinking female rats (Avchalumov et al., 2021). Taken together, these data reveal that alcohol-induced neuroimmune signaling causes persistent structural and functional mPFC synaptic adaptations to shift the region’s E/I balance towards a hyperexcitable state, possibly contributing to neuroimmune-associated vulnerabilities in developing neuropsychiatric disorders comorbid with chronic alcohol use.

This maladaptive plasticity may increase an individual’s susceptibility for developing a comorbid neuropsychiatric disorder; many neuropsychiatric disorders share similar disruptions to the same neuroimmune signaling pathways as is observed in patients with AUD. Supporting this idea, patients with bipolar disorder, MDD, and schizophrenia have elevated plasma levels of several pro-inflammatory cytokines and their receptors (e.g., C-reactive protein, IL-6, NLRP3, caspase-1, IL-1β, and IL-18) (Köhler et al., 2017; Lestra et al., 2022; Modabbernia et al., 2013), and show evidence of cortical plasticity and E/I imbalance (Duman et al., 2019; Laham and Gould, 2021; Mueller-Buehl et al., 2023). While the mechanisms underlying how the neuroimmune system contributes to the development of AUD and other neuropsychiatric disorders have yet to be fully elucidated, it is possible that the impact of repeated and prolonged pro-inflammatory cytokine signaling on synaptic transmission is a critical driver. As a result, one key avenue of current drug discovery efforts is focused on targeting the neuroimmune system to restore E/I balance to treat AUD and other substance use disorders (Farokhnia et al., 2020; Nwachukwu et al., 2023).

5. Conclusions

Therefore, there is a growing body of evidence that the neuroimmune system, in addition to its role as the first line of defense against toxins and pathogens, can also directly influence PFC synapses. Briefly, several neuroimmune factors, including IL-1β, TNF-α, IL-13 and IL-6, have been found to regulate neurotransmitter release and postsynaptic receptor expression and trafficking under both basal and pathological conditions (Zipp et al., 2023). They also facilitate pruning of pre- and postsynaptic terminals. Moreover, after an insult or injury pro-inflammatory A1 astrocytes show a reduced capacity for supporting synapse formation and function (Lian et al., 2015) in contrast to A2 astrocytes that release anti-inflammatory cytokines and neurotrophic factors to promote synaptic repair and growth (Liberman et al., 2018; Zamanian et al., 2012). Astrocytes, and to a lesser extent neurons, also secrete ECM molecules as well as their MMP degradation enzymes; pro-inflammatory cytokines, including IL-33, TGF-β, NF-κB, TNF-α, can alter the levels of both to bidirectionally regulate synaptic remodeling (Hamel et al., 2005; Namba et al., 2022; Nguyen et al., 2020). These are just a few examples of neuroimmune crosstalk within the tetrapartite synapse that have been characterized to date. It is likely that new mechanisms will continue to emerge, particularly as more studies consider the tetrapartite signaling microdomain as a whole rather than focusing on only one of the core structures. Recent advances suggest that it may also be important to consider other glial contributions; microglial processes have been observed in close proximity to tetrapartite synapses where they can participate in synaptic refinement, and oligodendrocyte precursor cells receive synaptic inputs and may also stimulate vesicular GABA release (Akinlaja and Nishiyama, 2024). Regardless, growing recognition of the neuroimmune system as a critical regulator of the PFC tetrapartite synapse provides strong support for targeting it as a means to restore E/I balance in AUD and other neuropsychiatric disorders (Erickson et al., 2019; Morrow et al., 2020).

Abbreviations:

A1

proinflammatory reactive astrocyte

A2

neuroprotective reactive astrocyte

Akt

protein kinase B

AMPAR

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

AUD

alcohol use disorder

CNS

central nervous system

CSPG

chondroitin sulfate proteoglycan

dlPFC

dorsolateral prefrontal cortex

E/I

excitatory/inhibitory balance

ECM

extracellular matrix

GABA γ

-aminobutyric acid

GABAAR

GABA A receptor

GABABR

GABA B receptor

GAD

glutamic acid decarboxylase

GAT

GABA transporter

GLAST or EAAT1

glutamate aspartate transporter

GLT-1 or EAAT2

glutamate transporter 1

GPCR

G-protein coupled receptor

Hapln

hyaluronan and proteoglycan link protein

IL

interleukin

IL-1β

interleukin-1 beta

IL-1R1

interleukin-1 receptor type 1

LTP

long-term potentiation

mGluR

metabotropic glutamate receptor

MMP

matrix metalloproteinase

mPFC

medial prefrontal cortex

MyD88

mitogen-activated protein kinase

NF-κB

nuclear factor kappa-light-chain-enhancer of activated B cells

NMDAR

N-methyl-D-aspartate receptor

PFC

prefrontal cortex

p38 MAPK

p38 mitogen-activated protein kinase

PI3K

phosphoinositide 3-kinase

PNN

perineural net

PSD-95

postsynaptic density protein 95

SNARE

soluble n-ethylmaleimide-sensitive factor attachment proteins receptor

TGF-β

transforming growth factor beta

TLR

toll-like receptor

TNF

tumor necrosis factor

VAMP

vesicle-associated membrane protein

vGAT

vesicular GABA transporter

vGLUT

vesicular glutamate transporter

vmPFC

ventromedial prefrontal cortex

Data availability

No data was used for the research described in the article.