Translational dysregulation as a mechanistic driver of cognitive, behavioral, and affective phenotypes in FXS and TSC

Abstract

Neurodevelopmental disorders (NDDs) are characterized by a spectrum of cognitive, behavioral, and affective morbidities, reflecting underlying disruptions in neural circuit development. Emerging evidence implicates translational dysregulation of synaptic proteins as a central mechanistic driver of these disordered phenotypes. Translational dysregulation entails atypical mechanisms of impaired initiation, elongation, and mRNA targeting, causing imbalanced protein synthesis. In NDDs specifically, translation of synaptic proteins is perturbed across developing neurons. Tuberous Sclerosis Complex (TSC) and Fragile X Syndrome (FXS) are notable monogenic NDDs, in which mutations in regulatory genes (Tsc1/Tsc2 in TSC, Fmr1 in FXS) disrupt signaling pathways that converge on mTORC1, PERK, and ERK/MAPK proteins, and result in excessive or insufficient translation of key synaptic proteins. These translational imbalances eventually compromise synapse formation, dendritic spine maturation, and neuronal network connectivity, contributing to deficits in learning, memory, social behavior, and emotional regulation. This review highlights the molecular mechanisms by which aberrant protein synthesis contributes to the cognitive and behavioral manifestations of TSC and FXS. Importantly, we also highlight cell-type-specific mechanisms, illustrating how translational dysregulation differentially impacts distinct neuronal and glial populations to shape behavioral and cognitive outcomes. Understanding the links between translational control and neurodevelopmental outcomes provides critical insights into the pathophysiology of these disorders and informs the development of targeted therapeutic interventions aimed at restoring synaptic protein homeostasis.

Introduction

Neurodevelopmental disorders (NDDs) comprise a heterogeneous group of conditions that affect brain development, leading to alterations in both neural structure and function. These disorders can be classified according to their clinical presentation and underlying genetic causes. Normal neurodevelopment depends on tightly regulated molecular and cellular processes that guide the formation of neural circuits and the establishment of brain function. Mutations in genes essential for these processes can disrupt neural development, resulting in long-lasting alterations in brain function and behavior (Parenti et al., 2020; Zhang and Wei, 2022). Consequently, NDDs affect multiple developmental domains and present with a broad spectrum of symptoms, including intellectual disability, communication deficits, learning difficulties, motor impairments, and challenges in social interaction (Francés et al., 2022).

Among the cellular mechanisms implicated in NDD pathogenesis, dysregulated protein synthesis has emerged as a critical contributor. Translation, the process by which proteins are synthesized from mRNA templates, involves coordinated stages of initiation, elongation, termination, and ribosome recycling that require numerous regulatory factors and protein complexes (Marintchev and Wagner, 2004). In neurons, local translation plays a particularly important role because these highly polarized cells rely on compartment-specific protein synthesis to support differentiation, synaptic development, and plasticity (Hafner et al., 2019; Ouwenga et al., 2018). Genetic and environmental perturbations can disrupt local translational control, leading to imbalances in signaling pathways that regulate neuronal growth and compartmentalization. Such alterations compromise neural development and have been increasingly linked to the pathophysiology of NDDs (Chen et al., 2019).

Emotional dysregulation (ED) is a prominent feature of many NDDs, although its severity and presentation vary across disorders. ED refers to difficulties in modulating emotional responses in a flexible, socially appropriate, and goal-directed manner. Individuals with NDDs frequently experience mental health challenges associated with impaired emotional regulation, including anxiety, depression, impulsivity, and aggressive emotional responses. Indeed, symptoms of anxiety and depression are reported in approximately 40–70% of children with NDDs (Tajik-Parvinchi et al., 2021). Deficits in emotional regulation can interfere with daily functioning, social relationships, and cognitive performance, substantially reducing quality of life (Davico et al., 2022). These processes depend on neural circuits involving the prefrontal cortex (PFC), amygdala, and broader limbic system, regions that are particularly vulnerable to molecular and cellular disturbances and are often atypically developed in NDDs (Birnie and Baram, 2022). Attention deficit hyperactive disorder (ADHD) is also among the most prominent NDDs and is characterized primarily by persistent patterns of inattention and/or hyperactivity-impulsivity (Scandurra et al., 2019). Importantly, NDDs frequently exhibit overlapping symptoms and comorbidity, with individuals often meeting diagnostic criteria for more than one disorder, such as autism spectrum disorder (ASD) and ADHD (De Giacomo et al., 2021; Karalunas et al., 2018; Taurines et al., 2012). This clinical overlap highlights the heterogeneity of NDDs and the potential for shared or convergent mechanisms underlying cognitive and behavioral phenotypes.

Cognitive dysfunction represents another major clinical feature across NDDs and encompasses impairments in higher-order cognitive processes such as attention, decision-making, information processing, learning, and working memory (Markousis-Mavrogenis et al., 2022). Intellectual disability is among the most prevalent manifestations of NDDs and was identified as a prominent feature in a cohort of 91 children with neurodevelopmental disorders (Bahal et al., 2024).

Cognitive impairments have also been associated with increased severity of emotional dysregulation, suggesting an important interaction between cognitive and emotional domains in affected individuals (Tajik-Parvinchi et al., 2021). In severe cases, cognitive dysfunction may impair the ability to perform everyday tasks and make routine decisions necessary for independent living (Bruderer-Hofstetter et al., 2020).

Among NDDs, Tuberous Sclerosis Complex (TSC) and Fragile X Syndrome (FXS), are particularly informative because they are monogenic disorders characterized by pronounced cognitive deficits and emotional dysregulation (Montanaro et al., 2024; Prather and de Vries, 2004). Both disorders arise from mutations in genes that regulate protein synthesis, resulting in direct disruptions of translational control (Bernard et al., 2022). Dysregulated protein synthesis has been strongly linked to the cognitive and behavioral abnormalities observed in these conditions (Tabaka et al., 2025). Their well-defined genetic etiologies make TSC and FXS valuable models for investigating how translational dysregulation contributes to NDD pathology. Animal models further support the relationship between altered protein synthesis and neurobehavioral dysfunction. NDD models with disrupted expression of key translational regulators frequently display behavioral phenotypes that parallel human symptoms. For example, Fmr1 knockout mice, a widely used model of FXS, exhibit heightened anxiety, hyperactivity, and resistance to environmental change (Spencer et al., 2005). However, behavioral phenotypes in Fmr1 knockout mice can vary depending on genetic background, with differences in social impairments reported across strains and genotypes (Spencer et al., 2011). Similarly, Tsc1/Tsc2 mutant mice demonstrate behavioral abnormalities, including increased avoidance behaviors and hyperarousal (Ehninger and Silva, 2011; Tabaka et al., 2025). However, heterozygous Tsc1/Tsc2 models can exhibit relatively subtle or inconsistent behavioral phenotypes, and some studies have reported no significant abnormalities in social approach, anxiety, or exploratory activity (Ehninger et al., 2008; Goorden et al., 2007; Yuan et al., 2012). These differences highlight the limitations of individual mouse models in fully recapitulating the heterogeneous clinical features of TSC and FXS. Nevertheless, these models provide valuable platforms for examining the neural mechanisms underlying emotional dysregulation and cognitive dysfunction and for evaluating potential therapeutic interventions. Despite these advances, the mechanistic relationship between aberrant translation and the development of emotional and cognitive symptoms across NDDs remains grounds to further investigate.

This review examines the mechanisms of protein synthesis dysregulation in TSC and FXS, with a particular focus on how alterations in translational control contribute to cognitive dysfunction and emotional dysregulation. By comparing the molecular pathways disrupted in these two disorders, we aim to highlight common and divergent mechanisms linking translational abnormalities to neurobehavioral outcomes. A deeper understanding of these pathways may provide important insights into the biological basis of cognitive and emotional impairments in NDDs and support the development of targeted therapeutic strategies for individuals with TSC and FXS.

NDD epidemiology, causes and pathophysiology: FXS, and TSC

Fragile X Syndrome (FXS), also known as Martin-Bell syndrome, is the most common monogenic cause of ASD and inherited intellectual disability. It results from a trinucleotide repeat expansion of the CGG sequence in the Fmr1 gene (Figure 1). Molecular genetic testing confirms the diagnosis by determining the number of repeats (Stone et al., 2023). The clinical presentation of FXS varies by sex, with males more commonly affected by ASD (30–50%) compared to females (25%). Females also experience milder epilepsy, seizures, and metabolic symptoms such as obesity than males (Ciaccio et al., 2017). Globally, FXS affects approximately 1 in 4,000 males and 1 in 8,000 females (Hunter et al., 2014; Lozano et al., 2016; Stone et al., 2023). The pathogenesis of FXS arises from hypermethylation and silencing of the Fmr1 gene due to CGG expansion. This results in a lack of fragile X mental retardation protein (FMRP), which regulates the translation of mRNA critical for synaptic plasticity (Penagarikano et al., 2007). FMRP inhibits local protein synthesis stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5 by binding specific mRNAs (Bhakar et al., 2012). Dysregulation of this signaling leads to synaptic dysfunction, forming the basis for the behavioral and cognitive phenotypes observed in FXS patients.

Figure 1: Overview of NDDs.

Description of the genetic and environmental etiology of NDDs, epidemiology and general pathophysiology of the initiation and progression of FXS and TSC. FXS is due to mutation in the Fmr1 gene, TSC is due to mutation in Tsc1 or Tsc2 gene. The pathophysiology of these diseases is dependent on dysregulation of protein synthesis, which alters cellular and molecular mechanisms underlying normal neurodevelopment.

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder caused by mutations in the Tsc1 (hamartin) or Tsc2 (tuberin) genes and is also highly comorbid with ASD (Figure 1). These mutations lead to a highly heterogeneous clinical presentation, affecting approximately 2 million people worldwide, with an estimated incidence of 1:6,000 to 1:17,000 live births (Annear et al., 2019; Winden et al., 2026). There is no consistent evidence of significant sex differences in the rates of behavioral problems, psychiatric disorders, or intellectual disability in TSC patients (de Vries et al., 2020). TSC causes tumors in multiple organs, including the brain, heart, skin, kidneys, and lungs, and is often associated with seizures, epilepsy, and TSC-associated neuropsychiatric disorders (TAND), which encompass behavioral, cognitive, intellectual, psychiatric, and psychosocial challenges (de Vries et al., 2015; Samanta, 2020; Winden et al., 2026). Mutations in Tsc1 or Tsc2 disrupt the inhibition of Ras homologue enriched in brain (RHEB), leading to sustained activation of the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of protein synthesis (Feliciano, 2020). This hyperactivation increases protein synthesis while disrupting stress-response pathways like PERK-eIF2α signaling, which normally arrests translation during cellular stress (Tyagi et al., 2015). Dysregulated translation underpins many of the phenotypes seen in TSC patients, including neurodevelopmental and behavioral impairments.

Mechanism of translation regulation under physiological conditions

Proteins are essential macromolecules involved in numerous physiological processes, including cell signaling and the formation and function of neural circuits (Kim and Jung, 2015; Tomé et al., 2021). Protein synthesis occurs through translation, a highly regulated process in which ribosomes decode mRNA to produce nascent polypeptides through the coordinated stages of initiation, elongation, termination, and ribosome recycling (Blanchet and Ranjan, 2022; Shrestha and Klann, 2022). Following translation, proteins undergo post-translational modifications that contribute to their functional diversity (Li et al., 2021). Given the central role of protein synthesis in cellular function, dysregulation of translation and its regulatory mechanisms has been associated with cellular dysfunction and various neurodevelopmental disorders (Jishi et al., 2021; Tahmasebi et al., 2019).

Multiple signaling pathways (Figure 2), including the PI3K/AKT, MAPK, mTORC1, and PERK pathways, play significant roles in translation regulation (Jishi et al., 2021; Roux and Topisirovic, 2018). These pathways are influenced by external factors such as brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), insulin, and insulin-like growth factor (IGF) (Schratt et al., 2004; Zheng et al., 2012).

Figure 2: Mechanisms of translation regulation.

The PI3K/AKT and ERK/MAPK signaling pathway increases protein synthesis by disinhibiting TSC’s inhibition on RHEB, an upstream activator of mTORC1 signaling pathway. mTORC1 activates translation initiation factors, therefore allowing protein synthesis to occur. RHEB also activates the PERK- eIF2α pathway to decrease protein synthesis. FMRP pathway represses protein synthesis by directly or indirectly inhibiting mRNA. The PERK pathway is activated during integrated stress responses, and it conserves cellular resources by inhibiting protein synthesis. PIP2 = phosphatidylinositol - (4,5) diphosphate (PIP2), PIP3 = phosphatidylinositol - (3,4,5) triphosphate, PI3K = phosphoinositide 3-kinase, PTEN = phosphatase and tensin homolog, AKT = alpha serine/threonine-protein or protein kinase B (PKB), RAS = rat sarcoma virus, RAF = rapidly accelerated fibrosarcoma, MEK = MAPK kinase, ERK = extracellular signal-regulated kinases, TSC = tuberous sclerosis complex, RHEB = Ras homologue enriched in brain, mTORC1 = mammalian target of rapamycin complex 1, 4E-BP1 = eukaryotic initiation factor 4E (eIF4E)-binding protein 1, eIF4E = eukaryotic initiation factor 4E, S6K1 = ribosomal protein S6 kinase, S6 = ribosomal S6 protein, PERK = protein kinase-like endoplasmic reticulum kinase, eIF2α = eukaryotic initiation factor 2α, eIF2B = eukaryotic initiation factor 2B, GDP = guanosine diphosphate, GTP = guanosine triphosphate, eIF4B = eukaryotic initiation factor 4B, eEF2K = eukaryotic elongation factor 2 kinase, MNK = MAP Kinase-interacting kinase, FMPR = Fragile X mental retardation protein, CYFIP = cytoplasmic FMR1 interacting protein.

The PI3K pathway regulates cell metabolism, proliferation, and migration. Upon activation, PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP₂), converting it into phosphatidylinositol-3,4,5-trisphosphate (PIP₃) (Fruman et al., 2017; Mukherjee et al., 2021). PIP₃ binds to and activates AKT (protein kinase B) via its pleckstrin homology domain (Manning and Toker, 2017). AKT then phosphorylates and destabilizes TSC2, a component of the tuberous sclerosis complex (TSC), and interferes with its interaction with TSC1, thereby indirectly releasing the inhibition on mTORC1. TSC is a GTPase activating protein (GAP) comprising TSC1, TSC2 and TBC1D7. As a GAP, TSC hydrolyses the active GTP-bound RHEB to RHEB-GDP, thereby inactivating RHEB (Xie et al., 2021). RHEB is a small GTPase that allosterically activates mTORC1 kinase activity. RHEB-GTP is an upstream activator of mTORC1 signaling pathway and its interaction with mTORC1 is essential for regulating fundamental cellular processes including protein synthesis (Zhong et al., 2022). mTORC1 increases protein synthesis and cell growth via downstream molecules that are associated with translation initiation: eIF4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase (S6K) (Jhanwar-Uniyal et al., 2019; Wang et al., 2024). mTORC1 promotes protein synthesis through the phosphorylation of 4E-BP1 and ribosomal protein S6 kinase (S6K). Phosphorylation of 4E-BP1 by mTORC1 releases eIF4E, enabling its role in initiating cap-dependent translation (Maracci et al., 2022). Additionally, S6K activation enhances the translation of 5’ Terminal Oligopyrimidine Tract (5’-TOP) mRNAs, which encode ribosomal proteins and elongation factors, further promoting protein synthesis (Hochstoeger et al., 2024; Wu et al., 2022). It also enhances translation through other factors including eukaryotic translation initiation factor 4B (eIF4B), and eukaryotic elongation factor 2 kinase (eEF2K) (Nguyen et al., 2023; Oddo et al., 2025).

The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cellular processes, including protein synthesis, and interacts with the mTORC1 signaling pathway. The major conventional MAPKs include extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK1/2/3), and p38 isoforms, which are activated by distinct extracellular and intracellular signals (Han et al., 2020; Ryu et al., 2024; Zeke et al., 2016). Among these, the RAS–RAF–MEK–ERK cascade provides an important link between growth factor signaling and mTORC1 activation through inhibition of the TSC. Together with AKT signaling, ERK-mediated inhibition of TSC promotes mTORC1 activity and thereby contributes to the regulation of protein synthesis (Cao et al., 2019; Roux and Topisirovic, 2018; Wang et al., 2024).

In addition to inhibiting TSC, ERK activates MAP Kinase-Interacting Kinase (MNK), which phosphorylates eIF4E, promoting protein synthesis (Genheden et al., 2015). Another crucial regulator of protein synthesis is the PERK-eIF2α signaling pathway. This is an integrated stress response (ISR) pathway, which is activated to arrest protein synthesis and conserve cellular resources during stress. RHEB is an upstream activator of PERK, which phosphorylates eIF2α (Boye and Grallert, 2020; Tyagi et al., 2015). GTP- bound eIF2 is associated with the small 40S ribosomal subunit during translation. For translation to occur, GDP-bound eIF2 exchanges GDF for GTP to form eIF2-GTP through the catalytic action of the guanine nucleotide exchange factor (GEF), eIF2B. Phosphorylation of eIF2α by PERK makes it inhibit the GEF activity of eIF2B, thereby preventing eIF2 from associating with ribosomal subunits, consequently inhibiting translation initiation (Marintchev and Ito, 2020). TSC proteins downregulate ISR by inhibiting RHEB, an upstream activator of PERK.

FMRP is a translational repressor and blocks mTORC1 effectors, albeit indirectly. FMRP inhibits protein synthesis by binding directly to mRNA or indirectly through other translation regulators. It binds to mRNA targets with specific sequences in their 3’ UTRs, preventing the assembly of translation machinery, and consequently suppressing protein synthesis (Athar and Joseph, 2020; Kurosaki et al., 2022). FMRP also interacts with Cytoplasmic FMR1 Interacting Protein (CYFIP), sequestering eukaryotic Initiation Factor 4E (eIF4E), and thereby preventing translation initiation. CYFIP interacts with both FMRP and eIF4E, playing a crucial role in the regulation of translation (Abekhoukh et al., 2017). Overall, the regulation of protein synthesis is a highly coordinated process involving multiple pathways. Dysregulation in these pathways can have significant consequences for cellular function and contribute to neurodevelopmental disorders. Understanding these mechanisms provides insights into cellular function and potential therapeutic targets for associated conditions.

Translation regulation during neurodevelopment

Neurodevelopment is governed by multiple tightly regulated processes, including protein synthesis. Dysregulation in translation or errors in its mechanisms play a significant role in the onset and progression of various neurodevelopmental disorders (Jishi et al., 2021). Critical stages of neurodevelopment, such as axon growth, dendrite formation, and neural maturation, rely on mRNA trafficking and localized protein synthesis within neurons (Fernandopulle et al., 2021). Translation regulation in neurodevelopment is also controlled by the various pathways mentioned above (Harnett et al., 2022; Rodrigue et al., 2025), and here, we will link each pathway to various steps in neurodevelopment.

The AKT/PKB signaling pathway regulates axon wrapping and the thickness of myelin sheath in the peripheral nervous system. Pharmacological inhibition of AKT in dorsal root ganglion cell culture decreases myelin sheath formation (Domènech-Estévez et al., 2016). AKT and the MAPK scaffold protein, JNK-interacting protein-1 (JIP1) colocalize in cortical axon growth cones and are involved in axon growth regulation. Downregulation of AKT and J1P1 in growth cones results in reduced axon growth (Dajas-Bailador et al., 2014). PTEN is a negative regulator of the AKT pathway, it dephosphorylates PIP₃, thereby regulates axon growth and prevents axon regeneration. Conditional knockout, knockdown, or pharmacological inhibition of PTEN in juvenile and adult mice causes axon regrowth, and this can be used as a therapeutic strategy for nervous system injuries (Huang et al., 2019; Ohtake et al., 2015). The ERK/MAPK signaling pathway is associated with several stages of neurodevelopment including neurogenesis, neural induction, neural patterning, neurite outgrowth, synaptogenesis, and gliogenesis (Albert-Gascó et al., 2020; Iroegbu et al., 2021).

FMRP interacts with several mRNAs in the developing cortex, especially those involved in MAPK, Wnt/β-catenin, and mTORC1 pathways (Casingal et al., 2020). It also regulates excitatory-inhibitory balance in embryonic motor circuits by enhancing the expression of inhibitory synaptic proteins during embryonic spinal development and regulates the generation of ventrolateral GABAergic interneurons in zebrafish models (Barker et al., 2022). FMRP silencing causes delayed neuronal development and maturation because of excessive transforming growth factor beta/bone morphogenetic proteins (TGFβ/BMP) activation. Perturbation in these processes decreases axonal growth cone guidance, resulting in perturbed neuronal network physiology in FXS patients (Kuznitsov-Yanovsky et al., 2022).

TSC, as a central regulator of the mTORC1 signaling pathway, is involved in regulating translation during neurodevelopment. Overexpression of TSC proteins in vitro and in the developing mouse brain inhibits axon formation. Meanwhile, TSC deficiency causes the formation of multiple and ectopic axons. Choi et al. showed that TSC is inhibited in axons to allow the synthesis of proteins required for axon growth, whereas TSC is not inhibited in the dendrites. This spatial and temporal regulation of TSC activity induces neuron polarity, which is an important stage of neurodevelopment (Choi et al., 2008). TSC pathway is also involved in other neurodevelopmental processes including axon guidance, synaptic formation, and axon regeneration (Chen and Aylett, 2025). mTORC1 signaling plays an important role in neuronal development and function by regulating actin dynamics, neurite and axon growth, and protein synthesis-dependent synaptic plasticity (Prem et al., 2024). Through its downstream effectors, S6K1 and 4E-BP1, mTORC1 promotes protein translation and contributes to axonal growth and regeneration (Jiang et al., 2023). More broadly, mTOR signaling is involved throughout neuronal development, including neuronal differentiation, migration, axon formation, dendritic growth, and synaptic development and plasticity. Consequently, dysregulation of mTOR signaling has been implicated in several neurodevelopmental disorders, particularly ASD and syndromic conditions such as TSC, PTEN-related disorders, and FXS (Winden et al., 2018). RHEB as an upstream regulator of mTORC1 activity, acts as a checkpoint or switch between anabolic and catabolic processes of the cell. This is critical to making developmental decisions during neurodevelopment (Duong et al., 2020). Overexpression of RHEB in mouse somatosensory cortex causes increased axonal connectivity and generalized seizure because of the hyperactivity of the mTORC1 signaling pathway (Proietti Onori et al., 2021). As mentioned above, RHEB activates both mTORC1 and PERK pathways. mTORC1 is known to increase protein synthesis while PERK pathway is an inhibitor of protein synthesis. The PERK- eIF2α pathway is activated during stress to conserve cellular resources and prevents the synthesis of damaged molecules. This pathway regulates stress-decided cell fate, autophagy, and apoptosis (Liu et al., 2015). Moreover, PERK increases neuronal apoptosis following surgical brain injury in rats. p-PERK and p-eIF2α were increased following the injury, and administration of PERK inhibitor prevented apoptosis (Wu et al., 2021). This signaling pathway might be playing a protective role by shutting down protein synthesis and preventing the survival of damaged neurons. The mechanism regulating RHEB-mediated switch between anabolism and catabolism in health and diseases is yet to be fully understood.

Translational Mechanisms Underlying Cognitive, Behavioral, and Affective Phenotypes in FXS and TSC

Translation regulation is necessary for cellular processes and normal neural functions. Mutation in genes that control the synthesis of mRNAs that are associated with translation regulation results in perturbed cellular processes, leading to disrupted neural circuits and computations (Table 1). This is the basis for the progression of neurodevelopmental disorders (Chen et al., 2019; Jishi et al., 2021). Pre and post translation regulations are also affected by environmental factors. As shown in previous studies, environmental factors such as stress influence protein synthesis. Similarly, other environmental insults such as heavy metals cause perturbation in the signaling pathways that regulate translation (Advani and Ivanov, 2019; Devi et al., 2022). Here, we outline the recent studies on the role of translation dysregulation in the pathogenesis of FXS and TSC

Table 1: Role of translational dysregulation in the pathogenesis of FXS and TSC.

Perturbations in key translational regulatory molecules and signaling pathways lead to either excessive or insufficient protein synthesis, depending on the affected node and cellular context. In FXS, loss of FMRP-mediated translational repression results in excessive protein synthesis through dysregulated mGluR5-, S6K1-, and ERK-dependent pathways, whereas in TSC, loss of TSC1/2 function primarily disrupts mTORC1 signaling but can also engage compensatory PERK-eIF2α stress responses that reduce protein synthesis in specific contexts. These translational imbalances alter synaptic protein composition, dendritic spine maturation, and circuit-level organization across hippocampal, cortical, striatal, and limbic systems. Consequently, defects in neuronal connectivity and synaptic plasticity contribute to the spectrum of cognitive, emotional, and behavioral impairments observed in neurodevelopmental disorders, including deficits in learning and memory, social dysfunction, emotional dysregulation, anxiety, impulsivity, and autism-like features.

NDD	Affected Molecules	Perturbed Pathways	Effect on Translation	Effect on Brain Circuits	Observed Symptoms	References
FXS	FMRP (loss of expression)	FMRP-mRNA binding / translational repression	Loss of translational inhibition → increased protein synthesis of synaptic mRNAs	Excess synaptic protein production; impaired activity-dependent synaptic plasticity; dysregulated synaptic scaling	Intellectual disability, learning and memory deficits, autism-like features, hyperactivity, seizures, altered vocal development, impaired auditory processing, reduced social preference, repetitive behavior, fine motor deficits	(Hale et al., 2021; Huber et al., 2002; Huebschman et al., 2020; Saré et al., 2016; Seo et al., 2022; Sidorov et al., 2013)
	mGluR5 signaling	mGluR-dependent translation cascade	Activity-dependent excess translation; exaggerated mGluR-LTD	Enhanced LTD; reduced synaptic stability; altered hippocampal plasticity	Learning and memory deficits; impaired cognitive flexibility	(Bear et al., 2004; Huber et al., 2002; Luo et al., 2023)
	S6K1 (ribosomal protein kinase)	mTOR-linked translational elongation pathway	Increased translation elongation	Ribosomal hyperactivity; altered protein synthesis rates	Cognitive impairment; synaptic dysfunction	(Aryal et al., 2021)
	mGluR7	ERK1/2–eIF4E pathway (mTOR-independent)	Suppression of protein synthesis via reduced initiation signaling	Normalization of synaptic plasticity and network excitability	Improved learning and memory; rescued behavioral phenotypes	(Kumar et al., 2024)
	Multiple interacting pathways	Combined mTOR, ERK, and translational control networks	Context-dependent dysregulation (regional/cell-type-specific increases in translation)	Disrupted PSD-95 expression; altered spine density and synaptic maturation	Social deficits; autism-like behavior; circuit instability	(Harbers et al., 2025; Huebschman et al., 2020; Stoppel et al., 2021)
TSC	TSC1/TSC2 (loss of function)	mTORC1 signaling pathway	Increased protein synthesis (baseline model); dysregulated translational homeostasis	Increased synaptic density (PV/SST interneurons); increased axonal density; altered E/I balance; abnormal network connectivity	Intellectual disability, learning and memory deficits, seizures, autism-like traits, anxiety, impulsivity, depression, aggression	(Bernard et al., 2022; Karalis et al., 2024; Tsai and Sahin, 2011)
	mTORC1 (hyperactivation via RHEB)	mTORC1-S6K signaling axis	Increased translation of synaptic and structural proteins	Aberrant LTP/LTD balance; altered synaptic maturation; excitatory/inhibitory imbalance	Cognitive inflexibility; seizures; ASD-like behavior	(Ehninger et al., 2008; Kosillo et al., 2019)
	PERK-eIF2α pathway	Integrated stress response (ISR)	Decreased global protein synthesis (context-dependent) due to translational repression	Stress-related synaptic dysfunction; circuit-level imbalance in specific cell types	Emotional dysregulation; sex-dependent anxiety/stress phenotypes	(Tabaka et al., 2025; Tyagi et al., 2015)
	ERK / mGluR5 signaling	ERK–mGluR-LTD pathway	mTOR-independent translational dysregulation; persistent synaptic depression	Sustained LTD; maladaptive plasticity in adulthood	Anxiety-like behavior; altered stress responsiveness; behavioral rigidity	(Potter et al., 2013)
	Nlgn1 (downstream effector)	mTORC1/4E-BP1-regulated synaptic protein synthesis	Excess translation of synaptic adhesion molecules	Synaptic overconnectivity / imbalance; altered excitatory transmission	Memory deficits; social deficits; ASD-like behaviors	(Chalkiadaki et al., 2023)
	Dopaminergic neurons (Tsc1 deletion)	mTORC1-dependent neuronal excitability pathway	Dysregulated local translation affecting excitability and dopamine release	Reduced intrinsic excitability; impaired dopamine signaling; cortico-striatal dysfunction	Cognitive inflexibility; motivational and behavioral deficits	(Kosillo et al., 2019)

ASD = autism spectrum disorder, FXS = fragile X syndrome, TSC = tuberous sclerosis complex, FMRP = fragile X mental retardation protein, mGluR5 = metabotropic glutamate receptor 5, S6K1 = ribosomal protein S6 kinase 1, ERK = extracellular signal-regulated kinase, MAPK = mitogen-activated protein kinase, mTORC1 = mechanistic target of rapamycin complex 1, TSC1/2 = tuberous sclerosis complex proteins 1 and 2, RHEB = Ras homolog enriched in brain, PERK = protein kinase R–like endoplasmic reticulum kinase, eIF2α = eukaryotic initiation factor 2 alpha, mPFC = medial prefrontal cortex, PV = parvalbumin, SST = somatostatin.

Fragile X Syndrome

In FXS, the X-linked Fmr1 gene has abnormal expansion of the CGG repeats, resulting in loss of FMRP expression (Jeon et al., 2017). FMRP regulates mRNA translation by inhibiting protein synthesis, resulting in increased synthesis of intracellular components (Darnell and Klann, 2013). FMRP binds to mRNAs through one of the three RNA binding domains and inhibits their translation. FMRP regulates synaptic proteins, and it is a key modulator of synaptic plasticity (Sidorov et al., 2013). Dysregulated mRNA translation has been shown to contribute to FXS phenotypes in the following ways:

a. Cognitive Dysfunction:

Fragile X syndrome (FXS), a leading inherited cause of intellectual disability, arises from mutation of the Fmr1 gene, which encodes the translational regulator FMRP (Quintin et al., 2016). Mechanistically, FMRP exerts cell-type-specific control over synaptic protein synthesis. Using translating ribosome affinity purification (TRAP) in hippocampal CA1 pyramidal neurons, (Hale et al., 2021) identified approximately 383 dendritically localized mRNAs associated with FMRP, the majority of which encode synaptic proteins. In another TRAP-seq study, (Thomson et al., 2017) identified more than 120 differentially translating mRNAs in CA1 pyramidal neurons from Fmr1-null mice, including excessive translation of Chrm4, which encodes the muscarinic acetylcholine receptor M4. Together, these findings strengthen the view that FMRP acts as a critical regulator of activity-dependent translation at synapses. However, while these data clearly establish widespread translational control by FMRP, the extent to which dysregulated translation alone is sufficient to account for cognitive impairment remains an open question. FMRP targets a broad repertoire of synaptic transcripts, suggesting that its loss may disrupt coordinated synaptic plasticity rather than single pathways in isolation. Given that hippocampal translational regulation is essential for long-term potentiation and memory consolidation (Lisman et al., 2017; Raven et al., 2021), aberrant protein synthesis in CA1 neurons likely contributes to the intellectual deficits observed in FXS. Importantly, this positions translational dysregulation not merely as a downstream consequence of synaptic dysfunction, but as a plausible mechanistic driver of impaired learning and memory.

Under physiological conditions, activation of group I mGluR stimulates local protein synthesis at synapses, which is required for several forms of synaptic plasticity. mGluR activation also regulates FMRP, including its phosphorylation state and association with target mRNAs, thereby relieving FMRP-mediated translational repression and allowing the synthesis of proteins required for activity-dependent synaptic remodeling (Bear et al., 2004; Darnell and Klann, 2013). Thus, mGluR signaling and FMRP function in a coordinated manner to maintain appropriate levels of synaptic protein synthesis and plasticity.

Consistent with the metabotropic glutamate receptor (mGluR) theory of FXS, loss of FMRP has been linked to exaggerated mGluR5 signaling in the hippocampus. In Fmr1 knockout mice, enhanced mGluR-dependent long-term depression (LTD) has been repeatedly observed, suggesting that unchecked protein synthesis downstream of mGluR activation disrupts synaptic stability (Bear et al., 2004; Huber et al., 2002; Luo et al., 2023). Mechanistically, increased mGluR5 expression reduces the surface availability of ionotropic glutamate receptors required for excitatory synaptic transmission, thereby shifting synaptic plasticity toward depression. Elevated mGluR5 signaling is further associated with increased ribosomal protein synthesis following Fmr1 mutation, reinforcing the idea that translational dysregulation amplifies activity-dependent synaptic weakening (Seo et al., 2022). However, translational and receptor-level findings are not entirely concordant across species. Radioligand studies in individuals with FXS have reported reduced mGluR5 availability compared to controls, contrasting with the elevated mGluR5 expression observed in mouse models. This discrepancy raises the possibility that compensatory receptor downregulation may occur in humans, or that developmental timing and chronic network adaptations reshape mGluR signaling differently across species. Such differences may help explain why mGluR5 inhibitors, including CTEP, successfully rescued cognitive and behavioral phenotypes in preclinical models but failed to demonstrate sustained efficacy in clinical trials (Michalon et al., 2012; Scharf et al., 2015; Stoppel et al., 2021). Rather than invalidating the mGluR theory, these translational gaps suggest that targeting mGluR5 alone may be insufficient once broader circuit-level and homeostatic adaptations are established.

Recent evidence highlights the role of mGluR7 as a translational regulator independent of FMRP. Activation of mGluR7 by the positive allosteric modulator AMN082 suppresses protein synthesis by reducing ERK1/2 and eukaryotic initiation factor 4E (eIF4E) phosphorylation, without affecting mTOR activity. Importantly, Fmr1 knockout mice treated with AMN082 exhibited improved learning and memory alongside rescued behavioral phenotypes, suggesting that mGluR7 may provide an alternative therapeutic entry point for correcting dysregulated translation in FXS (Kumar et al., 2024). The centrality of translation control to cognitive function is further underscored by multiple lines of evidence linking FMRP deficiency to learning and memory deficits. Fmr1 knockout mice display impaired fear learning (Saré et al., 2016), and human and cellular models demonstrate increased nonsense-mediated mRNA decay, which may contribute to intellectual disability and autism-like features (Kurosaki et al., 2021). At the molecular level, FXS is associated with enhanced translation elongation driven by increased ribosomal S6K1 activity. Pharmacological inhibition or genetic deletion of S6K1 restores normal elongation rates, corrects aberrant ribosome occupancy and mRNA expression, and may selectively normalize excessive protein synthesis without interfering with initiation (Aryal et al., 2021).

Collectively, these studies illustrate that multiple layers of translational dysregulation, spanning initiation, elongation, and receptor-mediated modulation, converge to impair synaptic plasticity and cognitive function in FXS. Targeting specific translational pathways, such as mGluR7 signaling or elongation control via S6K1, may therefore represent more precise and potentially effective therapeutic strategies than broader interventions like mGluR5 inhibition.

b. Emotional Dysregulation and Behavioral Abnormalities:

Beyond cognitive impairment, FXS is characterized by profound disturbances in emotional regulation and social behavior. Individuals with FXS frequently exhibit heightened anxiety, impulsive or aggressive responses, social-emotional immaturity, and autism-like behaviors. Emotional dysregulation affects approximately 40–60% of males and 20% of females with FXS (Bagni and Zukin, 2019), underscoring that affective instability represents a core component of the disorder rather than a secondary feature of intellectual disability. Emerging primate models further support a mechanistic link between translational dysregulation and behavioral pathology. In FMR1 mutant marmosets, exaggerated mGluR5 signaling has been associated with hyperactivity, seizures, altered vocal development, aberrant auditory processing, impaired social preference, and reduced fine motor performance, which are phenotypes that closely parallel clinical manifestations in FXS (Harbers et al., 2025). Importantly, transcriptomic analyses revealed dysregulation of FMRP target genes involved in synaptic transmission, mirroring molecular signatures observed in human FXS. These findings strengthen the argument that aberrant translation of synaptic transcripts disrupts circuit-level maturation underlying social and emotional behavior. Genetic reduction of mGluR5 signaling via GRM5 mutation prevented mutation-associated lethality, suggesting that excessive mGluR5 activity contributes substantially to pathological outcomes. However, the inability to rescue all behavioral phenotypes and the predominance of female subjects in the study highlight important limitations. These caveats suggest that while exaggerated mGluR5 signaling is a significant contributor, emotional and behavioral abnormalities likely arise from broader and developmentally dynamic translational disturbances that extend beyond a single receptor pathway. Indeed, converging evidence indicates that aberrant protein synthesis and disrupted synapse formation represent central pathogenic mechanisms in FXS (Harbers et al., 2025; Stoppel et al., 2021), reinforcing the view that translational dysregulation shapes both cognitive and affective phenotypes.

Deletion of ribosomal S6K1 in Fmr1 knockout mice provides compelling evidence that excessive translational signaling drives behavioral pathology. Loss of S6K1 normalized dysregulated translation-control pathways, including mTORC1, S6, eIF4B, and ERK, thereby correcting elevated protein synthesis. Importantly, S6K1 deletion also rescued exaggerated mGluR-dependent LTD and abnormal dendritic morphology, alongside improvements in motor coordination, skill acquisition, social interaction, and learning performance (Bhattacharya et al., 2012). These findings position S6K1-mediated translational control as a convergent node linking synaptic plasticity defects to behavioral abnormalities. Rather than a diffuse increase in protein synthesis, specific signaling cascades appear to orchestrate maladaptive plasticity in FXS.

Targeting upstream modulators of translation yields more nuanced outcomes. Inhibition of brain-expressed Src family kinases (SFKs) using saracatinib normalized elevated protein synthesis and corrected social and learning deficits in Fmr1 mutant mice; however, it failed to restore disrupted protein interaction networks or repetitive behaviors (Stamenkovic et al., 2024). This partial rescue suggests that while translational normalization is necessary for behavioral improvement, it may not be sufficient to reverse entrenched circuit-level abnormalities. Off-target effects or compensatory signaling among Src family members may further limit therapeutic specificity. Together, these findings underscore that distinct behavioral domains may be differentially sensitive to translational interventions.

At the synaptic level, structural abnormalities further illustrate the complexity of FMRP’s regulatory role. Fmr1 knockout mice exhibit increased PSD-95 accumulation and elevated spine density in cortical excitatory synapses, although many spines display immature morphology (Coulson et al., 2024). Treatment with the integrated stress response inhibitor ISRIB restored spine morphology and rescued social recognition deficits, potentially via increased GluA1 incorporation at postsynaptic sites. Notably, this study reported reduced global protein synthesis in Fmr1 knockout mice, contrasting with earlier reports of elevated translation (Bhattacharya et al., 2012; Harbers et al., 2025; Stoppel et al., 2021). The inability of ISRIB to rescue global protein synthesis despite correcting synaptic and behavioral phenotypes suggests that FMRP’s function may be context-, circuit-, or developmental stage-specific. Rather than globally suppressing translation, FMRP may fine-tune the synthesis of select synaptic proteins in a temporally and cell-type restricted manner. Cell-type-specific profiling further refines this model. Translational analysis of striatal medium spiny neurons (SPNs) revealed that increased de novo protein synthesis in the dorsolateral striatum of Fmr1 knockout mice enhances synaptic plasticity underlying repetitive behaviors (Longo et al., 2023). Direct pathway (D1 receptor-expressing) SPNs were identified as the primary contributors, with over 120 mRNAs exhibiting altered ribosome association. Mechanistically, enhanced eIF4E-eIF4G interactions in these neurons disrupt the balance between cortico-striatal direct and indirect pathways, providing a circuit-level explanation for repetitive behaviors. However, contrasting findings in cultured striatal neurons demonstrate reduced PSD-95 puncta and spine density following FMRP loss (Huebschman et al., 2020), again emphasizing that translational dysregulation does not manifest uniformly across cell types or experimental systems. Collectively, these studies reinforce translational dysregulation as a core mechanism mediating behavioral deficits in FXS. Yet they also reveal that the direction and magnitude of protein synthesis changes are highly context dependent. Rather than a simple model of “increased global translation,” FMRP deficiency appears to produce circuit- and cell-specific imbalances in translational control, which differentially impact social behavior, repetitive actions, learning, and synaptic maturation. It is also increasingly clear that translational dysregulation alone cannot fully account for the breadth of phenotypes observed in FXS. FMRP has several translation-independent functions, including direct modulation of ion channels such as Slack and BK, which regulate neuronal excitability and presynaptic neurotransmitter release independently of protein synthesis (Contractor et al., 2015). Together with FMRP’s roles in RNA transport and, in some contexts, chromatin regulation, these findings suggest that a complete understanding of FXS pathophysiology will need to account for both translational and non-translational functions of FMRP.

Tuberous Sclerosis Complex

In TSC, mutations in the Tsc1 or Tsc2 genes result in loss of function of the TSC protein complex, a key negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Through inhibition of mTORC1 signaling, the TSC complex normally restrains mRNA translation and regulates the synthesis of proteins required for synaptic development and maintenance (Bernard et al., 2022). Consequently, loss of TSC function leads to dysregulated protein synthesis and abnormal neuronal growth. Consistent with this model, Tsc1/2 deficiency has been associated with increased synaptic density in parvalbumin (PV)- and somatostatin (SST)-expressing cortical interneurons (Bernard et al., 2022), as well as increased axonal density (Karalis et al., 2024). These alterations are thought to contribute to the disrupted neural connectivity, cognitive impairment, and behavioral abnormalities characteristic of TSC (Tsai and Sahin, 2011). Dysregulated mRNA translation has been shown to contribute to TSC phenotypes in the following ways:

a. Cognitive Dysfunction:

Cognitive impairment is among the most common neuropsychiatric manifestations of TSC, encompassing intellectual disability, learning deficits, executive dysfunction, and autism-associated features. Although mTORC1 hyperactivation is a defining molecular hallmark of TSC, recent studies have challenged the assumption that TSC uniformly produces increased protein synthesis. In vivo and ex vivo investigations using transgenic heterozygous Tsc mutant mice (Saré et al., 2022) and hippocampal slice preparations (Auerbach et al., 2011) have instead reported reductions in protein synthesis. Using autoradiographic L-[1–14C] leucine labeling, Saré et al. (2022) demonstrated decreased rates of cerebral protein synthesis across multiple brain regions, a finding that appears paradoxical given the established role of the TSC complex as a suppressor of mTORC1-mediated translation. These observations suggest that translational regulation in TSC involves additional signaling mechanisms beyond mTORC1 alone.

One potential explanation is provided by the PERK-eIF2α pathway, which is responsible for regulating translational repression during cellular stress. TSC normally inhibits RHEB, an upstream activator of PERK. Consequently, while the loss of TSC function may simultaneously enhance mTORC1 signaling, it may relieve inhibition of the PERK pathway, thereby promoting translational repression through eIF2α phosphorylation (Tyagi et al., 2015) (Figure 2). This model is supported by findings in socially isolated mice with Tsc2 deletion in oxytocin receptor-expressing cells, where both mTORC1 and PERK signaling were hyperactivated. Importantly, activation of the RHEB-PERK axis appeared to dominate over mTORC1-mediated translational stimulation, resulting in an overall reduction in protein synthesis and driving sex-specific behavioral phenotypes (Tabaka et al., 2025). However, increased protein synthesis has also been reported in other Tsc2-deficient neuronal models, highlighting that the direction of translational changes may vary across experimental models and cellular contexts (Kelly et al., 2018; Nie et al., 2015). These findings highlight a recurring theme in translational disorders: alterations in global protein synthesis may reflect the net balance of competing translational pathways rather than the activity of a single signaling cascade. Thus, while enhanced mTORC1 signaling can promote protein synthesis, activation of alternative pathways such as PERK-eIF2α may counteract this effect and contribute to reduced translational output in specific contexts. This may help explain why some experimental models exhibit reduced rather than elevated protein synthesis despite robust mTORC1 activation.

The therapeutic implications of this dual-pathway model are significant. While rapamycin remains the prototypical strategy for suppressing mTORC1 hyperactivity, inhibition of PERK using GSK2606414 has also been shown to rescue behavioral deficits and normalize PERK-eIF2α signaling in TSC-related models (Dhir et al., 2023; Gundu et al., 2022; Tabaka et al., 2025). Although PERK inhibition has been proposed as a therapeutic strategy, its effects on mTORC1-driven synaptic protein synthesis remain unclear, suggesting that these pathways may regulate protein homeostasis through distinct or context-dependent mechanisms. Similarly, integrated stress response inhibitors such as ISRIB reverse the translational consequences of eIF2α phosphorylation and may represent a complementary approach for restoring translational homeostasis (Boretti and Banik, 2024; Rabouw et al., 2019; Zyryanova et al., 2021). Together, these findings suggest that therapeutic correction of cognitive dysfunction in TSC may require modulation of multiple translational pathways rather than exclusive targeting of mTORC1.

Beyond translational control, cognitive deficits in TSC are also linked to disruptions in neurotransmitter systems and network excitability. Tsc1 deletion in striatal dopamine neurons increases dopamine production while reducing dopamine release probability and evokes extracellular dopamine levels, primarily through decreased intrinsic excitability of dopaminergic neurons. These alterations were associated with impaired cognitive flexibility in Tsc1 knockout mice and were rescued by deletion of Raptor, a key component of mTORC1 (Kosillo et al., 2019). This finding suggests that dysregulated translation can influence cognition indirectly through modulation of neuromodulatory systems, extending the consequences of mTORC1 dysfunction beyond local synaptic protein synthesis. Cognitive impairment in TSC is also closely intertwined with epilepsy and abnormal cortical development. Cortical tubers and associated cellular abnormalities have long been implicated in intellectual disability and autism-like features observed in patients with TSC (Winden et al., 2026). Mechanistically, cortical tubers exhibit abnormal gamma-aminobutyric acid (GABA) receptor expression and impaired astrocytic glutamate transport, contributing to excitatory-inhibitory imbalance and seizure generation (Mizuguchi et al., 2021; White et al., 2001; Wong et al., 2003). Notably, rapamycin treatment reduced seizure severity and inhibited astrocyte overproduction in epileptic Tsc1 mutant mice (Zeng et al., 2008), further linking translational dysregulation to network dysfunction. These findings suggest that aberrant protein synthesis contributes not only to intrinsic neuronal abnormalities but also to broader alterations in circuit excitability that influence cognitive outcomes.

The importance of translational regulation for learning and memory is further illustrated by studies of synaptic plasticity. Mice with heterozygous deletion of Tsc2 exhibit deficits in hippocampus-dependent learning tasks, including the Morris water maze and contextual fear discrimination paradigms. These impairments were associated with abnormal long-term potentiation (LTP), specifically a lowered threshold for induction of late-phase LTP in hippocampal slices. Treatment with rapamycin normalized both synaptic plasticity and learning performance (Ehninger et al., 2008), indicating that excessive mTORC1 signaling contributes directly to memory dysfunction. Given the established requirement of tightly regulated protein synthesis for memory consolidation (Costa-Mattioli et al., 2009; Pearce et al., 2017; Scharf et al., 2002; Shrestha et al., 2020), these findings reinforce the concept that disrupted translational control represents a mechanistic driver of cognitive deficits in TSC.

Collectively, these studies reveal that cognitive dysfunction in TSC cannot be explained solely by mTORC1-mediated translational upregulation. Instead, converging evidence indicates that interactions among mTORC1, PERK-eIF2α signaling, dopaminergic regulation, synaptic plasticity, and network excitability collectively shape cognitive outcomes. The coexistence of findings showing both increased and decreased protein synthesis further suggests that translational dysregulation in TSC is highly context dependent. Consequently, therapeutic strategies aimed at restoring translational balance rather than simply suppressing protein synthesis may provide greater efficacy in addressing cognitive impairment.

b. Emotional Dysregulation and Behavioral Abnormalities:

Beyond cognitive impairment, TSC is associated with substantial disturbances in emotional regulation and behavior. Emotional dysregulation frequently co-occurs with ASD, ADHD, anxiety disorders, depression, mood disturbances, and aggression. Approximately 90% of individuals with TSC experience neuropsychiatric symptoms, with anxiety or depression affecting an estimated 47% of patients (Winden et al., 2026). These observations suggest that affective dysfunction represents a core component of TSC pathology rather than a secondary consequence of cognitive impairment. Although the neural circuitry underlying these symptoms remains incompletely understood, emerging evidence increasingly implicates dysregulated mRNA translation as a central contributor to emotional and behavioral abnormalities.

Animal studies have produced somewhat heterogeneous behavioral findings. In Tsc2 dominant-negative mutant mice, disrupted Tsc2 signaling was associated with increased anxiety-like behavior, reflected by avoidance of open arms in anxiety paradigms (Ehninger and Silva, 2011). In contrast, other Tsc2 mutant models demonstrated hyperactivity and impulsivity while exhibiting relatively normal anxiety-related behaviors (Yuan et al., 2012). These discrepancies may reflect differences in genetic background, developmental timing, or the specific neural circuits affected by Tsc2 disruption. Similar to observations in other neurodevelopmental disorders involving translational dysregulation, behavioral phenotypes in TSC likely emerge from circuit-specific alterations rather than a uniform molecular mechanism. Consequently, emotional dysregulation may manifest differently depending on the cellular populations in which translational control is disrupted.

Synaptic plasticity studies provide important mechanistic insight into how translational abnormalities contribute to behavioral dysfunction. Adult Tsc2 mutant mice exhibit elevated mGluR-dependent long-term depression (mGluR-LTD) and increased mGluR5 expression relative to adult wildtype animals. Interestingly, only juvenile Tsc2 mutants responded to rapamycin-mediated mTOR inhibition, whereas LTD in adult mutants appeared largely independent of mTOR signaling (Potter et al., 2013). Restoration of normal LTD in adult mutants required sequential inhibition of mGluR5 and ERK signaling using MPEP and U0126 prior to rapamycin treatment. These findings suggest that chronic Tsc2 deficiency induces adaptive engagement of parallel translational pathways that eventually bypass mTORC1. Consistent with this interpretation, recent work in human TSC disease models demonstrated that neuronal hyperactivity becomes increasingly resistant to mTORC1 inhibition during maturation as persistent transcriptional and epigenetic alterations emerge downstream of early mTORC1 dysregulation (Afshar-Saber et al., 2025). Notably, late administration of mTORC1 inhibitors failed to reverse neuronal hyperactivity despite partial correction of gene expression changes, indicating that pathological phenotypes can become uncoupled from their original mTORC1-dependent trigger over time. Collectively, these findings suggest that prolonged Tsc1/2 deficiency leads to compensatory engagement of parallel signaling pathways, allowing pathological translation and circuit dysfunction to persist independently of mTORC1 and potentially limiting the efficacy of mTOR-targeted interventions.

Evidence from downstream translational effectors further supports this concept. Overexpression of Nlgn1, a synaptic adhesion molecule regulated by the mTORC1/4EBP1 pathway, contributes to abnormal synaptic plasticity and behavioral dysfunction in TSC models. Correction of Nlgn1 overexpression restored mGluR-LTD, improved memory performance, and rescued social deficits (Chalkiadaki et al., 2023). Because Nlgn1 regulates excitatory synapse formation and maintenance, its normalization may restore synaptic architecture and transmission that are disrupted by excessive translational signaling. Interestingly, alterations in Nlgn1 expression and synaptic morphology have also been implicated in depressive-like phenotypes (Dang et al., 2018; Feng et al., 2016), raising the possibility that common translational mechanisms underlie affective dysfunction across multiple neuropsychiatric disorders. These findings further suggest that targeting specific translationally regulated proteins may offer greater precision than broad suppression of mTOR signaling.

Recent work has also highlighted the importance of cell-type-specific translational regulation in emotional behavior. Deletion of Tsc2 in oxytocin receptor-expressing cells within the medial prefrontal cortex produced sex-dependent responses to chronic social isolation stress, with males exhibiting increased stress susceptibility and females displaying relative resilience. Notably, PERK inhibition, but not rapamycin treatment, rescued social avoidance in female mutant mice. However, PERK inhibition in wildtype females reduced normal social preference, whereas rapamycin had minimal effects on social behavior (Tabaka et al., 2025). These findings suggest that different components of the TSC signaling network regulate distinct aspects of emotional behavior through divergent translational mechanisms. While mTORC1 hyperactivation remains a defining feature of TSC, PERK-dependent translational repression may be particularly relevant for stress responsiveness and social behavior. The contrasting effects of PERK inhibition in mutant and wildtype animals further emphasize that therapeutic modulation of translation must be carefully calibrated to avoid disrupting physiological translational control.

Collectively, these studies support translational dysregulation as a major mechanism underlying emotional and behavioral abnormalities in TSC. However, they also demonstrate that emotional phenotypes cannot be attributed solely to mTORC1 hyperactivation. Instead, converging evidence indicates that mTORC1, PERK, ERK, mGluR5, and downstream synaptic effectors interact in a developmental-, circuit-, and cell-type-specific manner to influence anxiety, social behavior, impulsivity, and stress responsiveness. Consequently, therapeutic approaches that restore translational balance across multiple signaling pathways may prove more effective than strategies focused exclusively on mTOR inhibition.

Convergent and Divergent Mechanisms between FXS and TSC

FXS and TSC arise from distinct genetic etiologies yet converge on dysregulated translational control as a central pathogenic mechanism. Both disorders exhibit enhanced mTORC1 signaling, altered phosphorylation of downstream effectors such as S6K and 4E-BP1, disrupted synaptic protein synthesis, aberrant dendritic spine morphology, and overlapping cognitive and behavioral phenotypes. In addition to convergence at the level of translational signaling, recent evidence demonstrates molecular crosstalk between the two disorders, including dysregulated FMRP degradation in TSC2-deficient neurons, further linking TSC and FXS pathways (Winden et al., 2023). Importantly, protein synthesis and degradation are interconnected processes that together maintain cellular proteostasis, and aberrant protein degradation has also been implicated in FXS and TSC and may contribute to disease phenotypes (Louros and Osterweil, 2016). These shared features support the idea that imbalanced translational drive, together with dysregulated protein degradation, may destabilize synaptic homeostasis during development.

Despite this convergence, the nature of translational dysregulation differs substantially. In TSC, mutations in TSC1 or TSC2 directly impair the GAP activity of the TSC complex, leading to constitutive RHEB activation and broad mTORC1 hyperactivation (Feliciano, 2020). This results in a primarily magnitude-based dysregulation of cap-dependent translation and cellular growth pathways. In contrast, FXS stems from loss of FMRP, an RNA-binding protein that confers transcript-specific translational repression. Rather than uniform upregulation, FXS is characterized by context-dependent and cell-type-specific alterations in protein synthesis, often exaggerated downstream of mGluR signaling (Luo et al., 2023). Additionally, emerging evidence suggests differential engagement of elongation control, ISR signaling, and synaptic pathway bias between the two disorders (Aryal et al., 2021; Coulson et al., 2024; Tabaka et al., 2025).

Thus, TSC reflects a failure of global metabolic restraint at the level of mTORC1 or PERK, whereas FXS represents a breakdown in synaptic translational precision. These mechanistic distinctions may underlie differences in therapeutic responsiveness, with direct mTORC or PERK inhibition demonstrating clinical benefit in TSC, while more targeted modulation of synaptic translation may be required in FXS.

Concluding Remarks

Protein synthesis is a tightly regulated process that is essential for neurodevelopment, synaptic maintenance, and circuit function in the adult brain. Disruption of translational control mechanisms is increasingly recognized as a central contributor to NDDs, particularly through mutations in genes encoding key regulatory proteins such as Tsc1/Tsc2 and Fmr1, which converge on pathways including mTORC1, PERK, and ERK/MAPK. Dysregulation within these signaling networks can lead to either excessive or insufficient protein synthesis, depending on the cellular context and developmental stage, ultimately impairing synaptic protein composition, dendritic spine maturation, and neuronal connectivity. These molecular alterations provide a mechanistic basis for the cognitive deficits, including impairments in learning and memory, as well as the emotional and behavioral abnormalities observed in disorders such as TSC and FXS.

While substantial progress has been made in identifying key translational signaling pathways involved in NDDs, important gaps remain in understanding how these mechanisms operate in a circuit- and cell type-specific manner. In particular, the identity and functional relevance of mRNAs selectively regulated by distinct translational pathways remain incompletely defined. Moreover, signaling nodes such as RHEB highlight the complexity of translational regulation, as they interface with both mTORC1-activating and stress-responsive inhibitory pathways such as PERK-eIF2α, potentially producing divergent outcomes depending on cellular state. This raises the possibility that translational control is dynamically reconfigured across developmental stages and neuronal populations, rather than functioning as a uniform regulatory system.

An additional challenge lies in the extensive redundancy and compensatory interactions among translational regulatory pathways. Disruption of a single signaling cascade may be buffered by parallel mechanisms, resulting in partial rescue or, in some cases, progressive network-level reorganization that renders pathology less sensitive to single-node interventions. Such adaptive changes may help explain why therapeutic strategies targeting mTORC1 alone are often insufficient in fully restoring cognitive or behavioral function in established disease states. Understanding how these compensatory mechanisms emerge across development and within specific neural circuits is therefore essential for designing more effective interventions.

In conclusion, translational dysregulation represents a convergent mechanistic driver of cognitive, emotional, and behavioral impairments in NDDs such as TSC and FXS. These phenotypes arise not only from global alterations in protein synthesis, but also from cell type-specific and circuit-level imbalances in translational control that evolve over time. More broadly, maintaining neuronal proteostasis requires a dynamic balance between protein synthesis and degradation, and disruption of either process may contribute to synaptic dysfunction and neurodevelopmental phenotypes. Thus, although translational dysregulation remains a central focus, altered protein degradation and turnover may also contribute to the composition and stability of the neuronal proteome. Elucidating how distinct neuronal populations integrate mTORC1, PERK, and ERK/MAPK signaling to regulate synaptic protein synthesis will be critical for advancing mechanistic understanding of NDDs. Ultimately, this knowledge will inform the development of targeted therapeutic strategies aimed at restoring translational homeostasis in a context-dependent manner, with the potential to improve both cognitive function and emotional regulation.

Methodology

Search strategy:

PubMed, Web of Science, and Scopus

Search terms

Fragile X Syndrome, FXS, or FMRP

Tuberous Sclerosis Complex, Tsc1, or Tsc2

Translational control, protein synthesis, or mRNA translation

Neurodevelopmental process

Synaptic plasticity

Behavior, cognition, emotional dysregulation, affective behavior, or neurobehavioral phenotype

Inclusion criteria

Studies were included if they:

1. Focused on FXS or TSC in human subjects or established animal models

2. Investigated mechanisms related to translational control or protein synthesis

3. Reported neurodevelopmental, synaptic, cognitive, behavioral, or affective outcomes

4. Were primary research articles or substantial mechanistic reviews

5. Were published in peer-reviewed journals in English

6. Were published within the last 15 years (2010 – 2025), except for some fundamentally important studies that were published prior to 2015.

Exclusion criteria

Studies were excluded if they:

1. Focused on idiopathic autism spectrum disorder or other NDDs without direct links to translational regulation

2. Examined non-neuronal tissues without relevance to brain development or function

3. Were purely descriptive clinical reports lacking mechanistic or behavioral analysis

4. Were conference abstracts, editorials, or opinion pieces

5. Were published outside the defined 15-year window, except for a few fundamental papers.

Highlights:

• Translational dysregulation is a convergent mechanism underlying TSC and FXS.

• mTORC1, PERK, and ERK/MAPK signaling shape neurodevelopment and synaptic plasticity.

• Cell-type-specific protein synthesis drives cognitive, emotional, and behavioral phenotypes.

• TSC and FXS exhibit distinct mechanisms that converge on disrupted translational control.

• Precision therapies restoring translational homeostasis may improve neurobehavioral outcomes.