The Eph-ephrin system in neuropsychiatric and neurodevelopmental disorders.

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Learn more: PMC Disclaimer | PMC Copyright Notice J Psychiatry Neurosci . 2026 Apr 14;51:1–12. doi: 10.1139/jpn-2025-0168 Search in PMC Search in PubMed View in NLM Catalog Add to search The Eph-ephrin system in neuropsychiatric and neurodevelopmental disorders A Bordignon A Bordignon a Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada Conceptualization, Investigation, Writing – original draft Find articles by A Bordignon a , JD Manduca JD Manduca a Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada Writing – original draft, Writing – review & editing Find articles by JD Manduca a , ML Perreault ML Perreault a Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing Find articles by ML Perreault a, ✉ Author information Article notes Copyright and License information a Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada ✉ Corresponding author: M.L. Perreault (email: [email protected] ) The authors declare no competing interests. This article is part of the Early Career Investigator Award collection. The article was originally published with minor errors (article type) that have now been corrected. ✉ Corresponding author. Roles A Bordignon : Conceptualization, Investigation, Writing – original draft JD Manduca : Writing – original draft, Writing – review & editing ML Perreault : Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing Received 2025 Aug 24; Accepted 2026 Jan 9; Collection date 2026. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) , which permits distribution and reproduction of the article in any medium, provided that the original publication is properly cited, the use is noncommercial, and no modifications or adaptations are made. PMC Copyright notice PMCID: PMC13078856  PMID: 41964204 Abstract Erythropoietin-producing hepatocellular (Eph) receptors are tyrosine kinase receptors that are canonically activated by their membrane tethered ligands, the ephrins. The Eph-ephrin system is critical in neurodevelopment, involved in processes such as neuronal growth and proliferation, axonal growth cone guidance, and cell survival. However, there is a significant knowledge gap in our understanding of the functional role of the Eph-ephrin system in later development, in both the adolescent and the adult brain. As various Eph receptor subtypes, and their associated ephrin ligands, are involved in the regulation of processes implicated in brain disorder pathogenesis, the Eph-ephrin system may represent an unexplored avenue for therapeutic target identification. Here, we will consolidate what is known about the Eph-ephrin system in synaptic plasticity, inflammation, and vascular permeability, linking the effects of specific ephrins and Eph receptors to depression and anxiety, autism, and schizophrenia. Novel insights into those Eph receptors with the most therapeutic promise will be provided and potential challenges of targeting these widely expressed receptor kinases discussed. Keywords: Eph receptors, ephrins, inflammation, synaptic plasticity, vascular permeability, neuropsychiatric disorders Erythropoietin-producing hepatocellular (Eph) receptors are the largest known family of transmembrane tyrosine kinase receptors. 1 These receptors along with their membrane tethered ligands, ephrins, are widely expressed in the brain and known to play important roles in neurodevelopment such as in neuronal growth and proliferation, axonal growth cone guidance, synapse formation, and cell survival. 2 , 3 Much less is known about the role of Eph-ephrin signalling in the adolescent and adult brain, although it has been implicated in in inflammation, vascular permeability, and synaptic plasticity. 2 These processes have been widely implicated in the pathogenesis of a number of neuropsychiatric and neurodevelopmental disorders indicating that this overlooked system may represent a unique avenue for therapeutic target discovery. In this review, we will therefore describe the functional roles of the Eph-ephrin system in brain, linking the known and postulated actions of specific ephrins and Eph receptors to the pathogenesis of depression and anxiety, autism, and schizophrenia. The most promising avenues for future therapeutic research in brain disorders will be highlighted alongside associated research challenges. The Eph/ephrin system There are currently 14 known Eph receptors in mammals, each of which falls into the A or B subfamilies, and characterized by the ephrin ligands to which they bind. 4 EphA receptors (EphA1-8 and EphA10) preferentially bind to five glycophosphatidylinositol (GPI)-anchored ephrin A ligands (ephrinA1-5), while EphB receptors (EphB1-4 and EphB6) preferentially bind to three transmembrane ephrin B ligands (ephrinB1-3), 5 , 6 although receptor-ligand binding can be promiscuous. 4 , 7 Eph receptor and ephrin structure Eph receptors are transmembrane proteins that contain both an intracellular and extracellular domain. There are four components which make up the intracellular domain of Eph receptors: a juxtamembrane sequence (JM), the tyrosine kinase domain (TK), a sterile alpha motif (SAM), and the PDZ-binding domain. 2 Phosphorylation of tyrosine residues on the JM, TK, and SAM domains of Eph receptors is induced by ligand binding. When the tyrosine residues of the JM are not phosphorylated, kinase activity of the receptor is inhibited. Upon ephrin binding however, the TK auto-phosphorylates and becomes active, and the JM becomes a docking site for downstream effector molecules. 5 , 8 – 10 The extracellular domain of Eph receptors is comprised of two fibronectin domains, a cysteine-rich region, and an N-terminal domain. The cysteine rich region contains the sushi and epidermal growth factor-like domain. 10 Along with the fibronectin domain, the cysteine-rich domain is involved in receptor dimerization, higher order clustering, and N-methyl-D-aspartate (NMDA) receptor interactions. 9 , 11 , 12 The N-terminal domain is made up of a sequence of 180 amino acids and acts as a ligand binding domain (LBD). 2 , 10 Eleven anti-parallel β-strands connected by differing loop strands are what comprise the LBD, which is highly conserved between the classes of receptors. 10 Class specificity of Eph receptors is conferred through the H-I loop structure, as the EphA receptors lack a four residue insert, which is expressed in the EphB receptors. 13 The ligand binding channels of the LBD are highly variable both within and between classes, and are comprised of the D–E and J–K loops 13 , 14 . The extracellular domain of ephrins are comprised of eight β strands folded into a β barrel, which acts as a receptor binding domain (RBD). 15 , 16 The G-H loop of the RBD is a long loop, which binds to the ligand binding channel of the Eph receptor. 16 While both types of ephrins contribute to reverse signalling, the ephrin-A ligands consist solely of extracellular components and are tethered by a GPI anchor, whereas ephrin-B ligands have an intracellular domain. 2 The ephrin-B intracellular domain is highly conserved across ephrins and made up of an 80 amino acid long tail and contains five tyrosine residues within its PDZ-binding domain, which enables reverse signalling within the ligand bound cell. 17 , 18 Eph-ephrin signalling Between neighboring cells, ephrins and Eph receptors can act as in trans ligands for each other. 2 Forward signalling involves the transduction of signals downstream of Eph receptor activation, occurring in the cell expressing the Eph receptor, and resulting in cell repulsion. 2 This is in contrast to reverse signalling, which is the transduction of signals downstream of ephrin activation, and occurring in the cell expressing the ephrin, to elicit either cell repulsion or adhesion. 2 These Eph-ephrin interactions can occur simultaneously resulting in bidirectional signalling, 2 and these interactions also lead to the formation of Eph-ephrin dimers and multimers. 15 , 19 The clustering size of these Eph-ephrin complexes correlate directly to the strength of the signal. 5 LBD–LBD and sushi–sushi interactions between Eph receptors in cis work to stabilize the oligomer 12 and allow for the recruitment of Eph receptors outside of the cluster. 20 While both A and B class receptors can be recruited to these clusters, it has been suggested that the clustering properties of each receptor may vary within classes. 16 On the same cell, ephrins can act on Eph receptors in cis , which has been thought to prevent Eph receptor clustering and reduce signal strength. 21 , 22 Reverse signalling cascades can also be induced by ephrins independent of Eph receptors, through in cis interactions with a wide variety of other membrane associated proteins. 23 , 24 The outcome of forward signalling can be highly variable and depends on factors such as receptor and ligand class and subtype, cellular expression of the receptor, and size of the receptor cluster. The tyrosine residue phosphorylation in the JM domain mediates signal transduction through Src homology 2 (SH2)-containing proteins such as non-receptor Src family kinase (SFK), Abl family kinase (AFK), and the adaptors Nck and Crk. 25 , 26 Eph-ephrin-mediated receptor activation also regulates the activity of guanine nucleotide exchange factors (GEFs) such as the ephexin 27 and Vav 28 families, and GTPase-activating proteins (GAPs) such as a2-chimerin 29 and phosphoinositide 3-kinase (PI3K). 27 Through these effector proteins, Rho and Ras family GTPases along with Akt signalling are modulated, which influence cell survival and morphology. 30 The EphA2 receptor also has the unique property of non-canonical forward signalling through ligand-independent phosphorylation of the serine 897 residue by Akt. 31 Although lacking an intracellular domain, A class ephrins employ reverse signalling to influence neuronal function, synaptic growth and arborization, learning and memory, cell proliferation, and neurogenesis. 32–35 Despite the mechanisms underlying these effects being poorly understood, proteins such as the p75 32 neurotrophic receptor and tropomyosin receptor kinase B (TrkB) receptor 33 have been reported to interact with A class ephrins following Eph receptor binding to modulate axon branching and guidance through ephrin reverse signalling. Conversely, the B class ephrins can mediate reverse signalling directly following Eph receptor binding. Eph receptor binding to the ephrin RBD results in the phosphorylation of intracellular domain residues via rapid recruitment and activation of SFKs. 36 This in turn allows for the binding of SH2-containing proteins 37 to influence synapse formation through dendritic spine morphogenesis. 38 PDZ-containing proteins are able to bind to the PDZ-binding domain, which allow for modulation and maintenance of neural progenitor cells. 39 Eph-ephrin regulation of neuroplasticity, inflammation, and vascular permeability The Eph-ephrin system has been linked to a number of neurobiological processes, such as neurogenesis, synaptic plasticity, vascular permeability, and neuroinflammation. These processes have been widely reported to play key roles in brain disorders such as depression 40 and SZ, 41 as well as in autism. 42 Together these findings suggest a potential important role for the Eph-ephrin system in the pathogenesis of brain disorders; however, this relationship has been poorly studied. In this section, we will therefore first describe what is presently known about the involvement of the Eph-ephrin system in neuroplasticity, inflammation and vascular permeability and then highlight the connections to brain disorder pathogenesis. Synaptic plasticity Synaptic plasticity is the brain's ability to remodel and restructure synapses, most often in response to developmental growth, environmental stimuli, and injury, 11 and which impacts on processes such as long-term potentiation (LTP) and long-term depression. 11 Disruptions to synaptic plasticity can also impair adaptability to environmental stimuli, 11 which is often a key characteristic of brain disorders. In schizophrenia, for example, there is a notable suppression in the evoked auditory and visual neuronal gamma band oscillatory response that has been linked to impaired glutamatergic signalling. 43 Glutamatergic receptor signalling is a critical component of synaptic function 11 and studies have linked ephrin B2-EphB2 receptor signalling to LTP via the regulation of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity. 44 – 46 In mouse hippocampal neurons, ephrin B1 binding to the EphB2 receptor promoted the association of the receptor to the GluN1 subunit of the NMDA receptor, inducing the formation of excitatory synapses. 11 Similarly, when the ephrinB1-EphB2 receptor interaction was disrupted in the mouse hippocampus, mossy fiber-CA3 synapse LTP was inhibited. 44 In EphB2 receptor knockout (KO) mice, tetanus-induced LTP is reduced in both the hippocampal CA1 and dentate gyrus compared to wildtype mice. 46 The effects of the EphB2 receptor in synaptic plasticity may also be mediated, at least in part, by its effects on dendritic spine morphogenesis. In vitro, double EphB1 and EphB2 receptor deficient hippocampal neurons show deficiencies in mature dendritic spine formation. 47 On the other hand, activation of EphB2 receptor forward signalling in cultured hippocampal neurons induces dendritic spine formation, with the GTPases Rac1 and RhoA being implicated as mediators of this effect. 48 , 49 Other studies have also shown an association between ephrin B2 and glutamatergic signalling. Primary hippocampal neurons derived from ephrin B2 KO mice showed enhanced constitutive AMPA receptor internalization and a reduction in hippocampal synaptic transmission. 45 Furthermore, ephrin B2 was shown to have neuroprotective properties, preventing impairments in synaptic plasticity, behaviour, and memory caused by infusion of pathogenic anti-NMDA receptor antibodies. 50 Activation of the EphA4 receptor in mouse hippocampus, which is highly expressed on hippocampal dendritic spines, promotes spine retraction via activation of astrocytic ephrin A3, whereas the absence of EphA4 receptors results in abnormalities in spine morphology. 51, 52 EphA4 receptor-mediated hippocampal spine retraction is also induced following activation by ephrin A1 and shown to be mediated by the downstream signalling proteins Cdk5 and ephexin-1, 53 and potentially through a downregulation of brain derived neurotrophic factor (BDNF) signalling. 54 In seeming contrast to these studies, there is evidence that both the EphA4 receptor and ephrin A3 are necessary for the induction of stimulus-induced hippocampal LTP. 55 However, while EphA4 receptor forward signalling was shown to be responsible for hippocampal spine retraction, the observed effects on LTP were shown to be mediated by EphA4 receptor-induced reverse signalling through ephrin A3, 55 with the ephrinA3-EphA4 receptor interaction reducing glial glutamate transporter expression and glutamate uptake. 55 Antagonism of the EphA5 receptor in hippocampal slices of mice also led to impaired LTP, and learning and memory and context-dependent fear conditioning deficits, 56 , 57 whereas EphA5 receptor activation produced LTP-like increases in synaptic transmission. 57 Together these findings suggest a role for both EphA and EphB receptors in the regulation of glutamatergic signalling and LTP. Whereas the EphB2 receptor has been demonstrated to positively regulate LTP and dendritic spine formation, EphA receptor effects appear to be more complex, involving both forward and reverse signalling. Vascular permeability and inflammation Vascular permeability of the blood brain barrier (BBB), a semipermeable membrane that acts as the main site of blood exchange to the CNS, 58 and inflammation are hallmarks of numerous brain disorders such as depression, schizophrenia, and autism. 59 , 60 The BBB, which consists of endothelial cells, astrocytes, and pericytes, creates tight junctions between endothelial cells restricting the passage of substances from the blood into the brain. Transmembrane bridging proteins such as claudins and occludins, in conjunction with periplast attachment zonula occludens (ZO) proteins and junctional adhesion molecules, also play key roles in maintaining BBB function. 58 Breakdown in BBB function, such as through innate inflammatory immune responses, enhances barrier permeability. 58 Claudin, ZO, and cadherins are key regulators of BBB function that interact with Eph receptors and ephrins expressed in endothelial cells to modulate both tight junctions and adherence junctions. 58 , 61 Recently, ephrin A1 activation of the EphA4 receptor has been shown to decrease both ZO-1 and claudin-5 expression through activation of the Rho/ROCK pathway both in human brain microvascular endothelial cells and an in vitro mouse stroke model cerebral tissue. 62 ROCK signalling has been shown to promote the release of inflammatory cytokines that have been linked to BBB disruption, 58 , 63 with the inhibition of the Rho/ROCK pathway leading to decreases in inflammatory responses and preventing deterioration of BBB function. 64 – 66 Specifically, Feng and colleagues 65 demonstrated that inhibiting the Rho-A/ROCK pathway repaired lipopolysaccharide (LPS)-induced BBB damage in C57 mice. SFK-dependent ephrin B1 phosphorylation has also been shown to lead to the disruption of tight junction efficacy via in cis interactions with claudins. 18 , 67 The ephrin A1-EphA2 receptor interaction plays an important role in vascular function and permeability; however, most of the work has been done in cancer models and in tissue other than the brain. For instance, in HT29 colon cancer cells, 68 ephrin A1 activation of the EphA2 receptor induces the phosphorylation of claudin-4, attenuating claudin's association with ZO-1 and disrupting tight junction function. 68 The Eph-ephrin system has also been implicated in modulating vascular permeability through adherens junctions. 61 In MCF-10A breast epithelial cells, EphA2 receptor overexpression decreased E-cadherin localization at adherence junctions through RhoA-dependent activity, decreasing junction stability. 69 In primary human endothelial cell culture, administration of ephrin A1 also destabilized adherence junctions through a decrease in vascular endothelial cadherin expression. 70 The EphA2 receptor regulation of vascular permeability appears to be tightly coupled to inflammation in the brain ( Fig. 1 ). In mouse primary brain endothelial cells, EphA2 receptor expression is upregulated in response to the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and lymphotoxin alpha. 70 This study also showed that in primary brain endothelial cells derived from EphA2 receptor KO mice, there was a suppressed neuroinflammatory response to Plasmodium berghei ANKA infection, as shown by a marked decrease in NF-κβ phosphorylation and TNF-α secretion compared to wildtype cells. 70 Proinflammatory cytokines, including TNF-α, have been shown to lower the integrity of both tight and adherens junctions through modulation of the expression and localization of key junction proteins, 71 potentially through NF-κβ-dependent mechanisms. 72 , 73 Importantly, while changes to the mRNA expression of other Eph receptors and ephrins are seen in non-brain endothelial cell tissue in response to LPS-induced inflammation in rats in vivo , only changes in EphA2 mRNA expression were observed in the brain. 74 Fig. 1. Open in a new tab Regulation of blood brain barrier permeability and inflammation by the EphA2 receptor. Activation of EphA2 receptor signalling promotes the destabilization of tight and adherens junctions, overall enhancing vascular permeability and inflammation. EphA2 induces the phosphorylation of claudin-4, promoting dissociation with ZO-1 and subsequent tight junction destabilization. EphA2 receptor activation also promotes the activity of proinflammatory cytokines, TNF-α and LT- α, and through a NF-κB-dependent mechanism, leads to reductions in the expression of key junction proteins, promoting destabilization. Lastly, the EphA2 receptor reduces E-cadherin localization to the adherens junction through a RhoA-dependent mechanism, promoting destabilization. Blue arrows and red arrows indicate negative and positive regulation, respectively. Abbreviations: blood brain barrier = BBB; lymphotoxin-alpha = LT-α; tumour necrosis factor-alpha = TNF-α; nuclear factor-kappa B = NF-κB; zonula occludens-1 = ZO-1. Schematic created in BioRender. While further investigation is clearly required, these limited findings implicate the EphA2 receptor in BBB permeability and these effects are coupled to inflammatory responses, a potentially important characteristic of this receptor that could be of particular relevance to a variety of brain disorders and diseases that display pathogenic inflammation. The Eph-ephrin system in brain disorders Alterations in synaptic plasticity, inflammatory processes, and vascular permeability are all key features of brain disorder pathogenesis. In this section what is known about the involvement of the Eph-ephrin system in anxiety and depression, autism, and schizophrenia will be described with key findings shown in Table 1 and Fig. 2 . Fig. 2. Open in a new tab Involvement of Eph/ephrin signalling in brain disorders. (A) Eph/ephrin signaling via various effector molecules influences alterations in synaptic plasticity, inflammation, and vascular permeability that may contribute to the development of a neuropsychiatric or neurodevelopmental disorder. (B) Eph receptors and ephrins with a known or predicted involvement in autism, depression and anxiety, or schizophrenia are shown. Blue arrows and red arrows indicate positive and negative regulation, respectively. Blue arrows and red arrows indicate negative and positive regulation, respectively. Abbreviations: GAPs = GTPase activating proteins; GEFs = guanine nucleotide exchange factors; GTPases = guanosine triphosphatases. Schematic created in BioRender. Table 1. The Eph-ephrin system in neuropsychiatric and neurodevelopmental disorders. Group Author Receptor/ligand Focus Experimental model Anxiety, depression Attawood et al. 86 EphB2 Neuropsin, FKBP5 , protein expression, glutamatergic signalling Mice, neuropsin KO, acute stress, chronic stress Li et al. 80 EphA4/Ephrin A3 Protein expression, stress susceptibility Rats, CUMS stress Li et al. 81 EphA4 Myelination, protein expression, stress responses Rats, CUMS, EphA4 knockdown, human brain tissue Zhang et al. 83 EphB2 Stress susceptibility, protein expression Mice, CSDS, PFC EphB2 knockdown Zhang et al. 54 EphA4 Protein expression, ephexin1, stress susceptibility Mice, CSDS Zhang et al. 89 EphB2 Glutamatergic signalling, stress susceptibility Mice, CSDS, amygdala EphB2 KO Zhen et al. 82 EphB2 Glutamatergic signalling, neurogenesis, cAMP, CREB, BDNF Mice, EphB2 KO Autism Butler et al. 94 , 95 EphA3, EphA4, EphA6, EphB2, EphB6 Genetic risk factors Human (autism), genetic studies cumulative database Eid et al. 98 EphA4/Ephrin A2 TRIO , Rho signalling, cytoskeletal structure, GABAergic signalling Mice, conditional Trio deficient Kuo and Liu 97 EphA4/Ephrin A5 Receptor expression, compartmental organization, corticostriatal pathway Mice, valproic acid Li et al. 108 EphB6 Vitamin B 6 homeostasis, gut microbiota Mice, EphB6 KO Suda et al. 96 Ephrin A4, B3 mRNA expression, receptor expression Human (autism), anterior cingulate and primary motor cortex tissue Sutley-Koury et al. 107 EphB2/Ephrin B1 Astrocyte function, parvalbumin, synapse development Mice, EphB2 KO Wurzman et al. 104 Ephrin A2, A3 Autism spectrum disorder pathology Mice, Ephrin A2/A3 double KO Yan et al. 101 EphA7/Ephrin A5 Ash1l , receptor expression Mice, Ash1l haplo-insufficient Schizophrenia Blokland et al. 120 EphB2 MIR137 Human (SZ), MRI Jézéquel et al. 124 EphB2 Glutamatergic signalling, protein expression Mice, GluN1 KO, primary hippocampal neurons; rat, hippocampal tissue; Human (SZ), serum Koskuvi et al. 126 EphA3, A5 Astrocyte function, receptor expression Human iPSC neuron-astrocyte co-culture (SZ) and iPSC astrocyte transplantation, Mice Rag1 KO Ripke et al. 117 EphB2 Genetic risk factors Human (SZ), genome-wide association study Ripke et al. 118 EphB2 Genetic risk factors Human (SZ), genome-wide association study Saia-Cereda et al. 121 Ephrin B Protein expression and phosphorylation Human (SZ), corpus callosum tissue Sailana et al. 127 EphA6 DISC1 , synapse formation, protein expression Rats, DISC1 overexpressing Su et al. 115 EphB1, EphB2 Genetic risk factors Human, genome-wide association study Wu et al. 116 EphB2 Genetic risk factors, MIR137 Human, genome-wide association study Zhang et al. 122 EphB2/ephrin A5 OPCML , dendritic spine morphology, cofilin Mice, OPCML KO Open in a new tab Note: Ash1l, ASH1-like histone lysine methyltransferase; CSDS, chronic social defeat stress; CUMS: chronic unpredictable mild stress; DISC1, disrupted in schizophrenia 1; Eph, erythropoietin-producing hepatocellular; FKBP5, FK506 binding protein 5; iPSC, induced pluripotent stem cell; KO, knockout; MRI, magnetic resonance imaging; OPCML, opioid-binding cell adhesion molecule-like; SZ, schizophrenia. Anxiety and depression Mood disorders are a group of disorders characterized by a persistent disturbance to emotional state. While there are genetic factors that can contribute to mood disorder risk, a major risk factor associated with mood disorders is environmental stress, particularly during critical periods of development. 75 The underlying pathology of mood disorders is highly heterogenous; however, alterations to neurotransmission, 76 synaptic plasticity, 77 neuroinflammation, 78 and vascular permeability 79 have all been reported. Some preclinical evidence suggests that disruption to Eph-ephrin system functions with stress exposure may be involved in depression pathogenesis. For example, in rats using the chronic unpredictable stress (CUS) paradigm, stress-susceptible, but not stress-resilient, rats exhibited a downregulation of EphA4 receptor expression and an upregulation of ephrin A3 in the hippocampus. 80 These changes were posited to be a potential mechanism for the remodeling of neuronal dendrites and spines, as well as altered glutamate signalling, observed following CUS, 80 with previous research linking ephrin A3-EphA4 receptor forward signalling to spine retraction 51 and reverse signalling to reduced astrocytic glutamate transporter expression 55 as described above. Furthermore, treatment with the antidepressant fluoxetine reversed these alterations in expression in drug responsive animals, 80 indicating a direct or indirect link between serotonergic signalling and EphA4 receptor and/or ephrin A3 transcription. In contrast to these findings, another study in mice that were exposed to CUS showed elevated hippocampal EphA4 receptor levels in pyramidal neurons that were associated with neuronal demyelination. 81 Furthermore, depression-like behaviour and synaptic deficits following stress were alleviated following EphA4 receptor knockdown. 81 These findings were further supported by postmortem analysis of individuals that had depression, in which the expression of the EphA4 receptor appeared to be related to the degree of neuronal demyelination. 81 In agreement with these findings, another study explored the role of the EphA4 receptor in a mouse model of chronic social defeat stress (CSDS) where they showed greater proportion of activated EphA4 receptor and its downstream effector ephexin-1 in the prefrontal cortex and hippocampus of stress susceptible mice, as well as in learned helplessness rats. 54 Following administration of the EphA4 receptor antagonist rhynchophylline to susceptible CSDS mice, ephexin-1 phosphorylation was normalized and a rapid antidepressant effect was observed. 54 The conflicting CUS findings in hippocampal EphA4 receptor expression in rats and mice may indicate species or procedural differences. However, overall evidence suggests a pro-depressive effect of EphA4 receptor activation in line with the previously described known role of the receptor in dendritic spine retraction and the reported reduction in spine densities in depression. 77 In contrast to the EphA4 receptor, the EphB2 receptor has been reported to have antidepressant-like properties. EphB2 receptor KO mice display both depression-like behaviours and disruptions in spatial memory. 82 At a cellular level, these mice exhibit fewer progenitor neurons, lower cAMP response element-binding protein (CREB) phosphorylation and BDNF expression in the hippocampus, alongside an elevation in NMDA receptor subunit B2 (GluNB2) expression. 82 The cellular and behavioural changes resulting from EphB2 KO were reversed by GluNB2 antagonism, suggesting that the EphB2 receptor may play a role in downregulating hippocampal GluNB2 to attenuate depression-like behaviour and maintain memory function. 82 In mice exposed to CSDS, those that were stress susceptible exhibited reduced EphB2 receptor expression in the prefrontal cortex. 83 To demonstrate a causal role for the EphB2 receptor in mediating depression like behaviour, activation of the receptor in the prefrontal cortex by ephrin B1 was antidepressant in susceptible CSDS mice, whereas prefrontal cortical knockdown of the EphB2 receptor promoted stress susceptibility to CSDS. 83 The antidepressant effects of EphB2 receptor activation were associated with normalization of dendritic spine densities. 83 There have also been observed increases in EphB2 receptor expression in the hypothalamus of mice that expressed LPS-induced depression-like behaviour. 84 The EphB6 receptor has also been suggested to be involved in stress-associated pathology as CUS-exposed mice show elevated EphB6 receptor expression in the prefrontal cortex. 85 Of all the Eph receptors, only the EphB2 receptor has been studied in anxiety responses. As described earlier in the review, the EphB2 receptor has been reported to promote excitatory NMDA receptor signalling. In mice deficient in neuropsin, a protease responsible for cleaving the EphB2 receptor and promoting its dissociation from NMDA receptors, elevated anxiety-like behaviour, EphB2 receptor-NMDA coupling, and FKBP5 expression in the amygdala were observed, 86 a gene heavily implicated in anxiety disorders, 87 depressive disorders, 88 and post-traumatic stress disorders. 88 These characteristics were all normalized upon intra-amygdala administration of neuropsin. 86 While together these findings linking the EphB2 receptor in amygdala to anxiety are associative, another study demonstrated that knockdown of the EphB2 receptor in the amygdala of CSDS mice produced an antidepressant-like effect, and prevented the stress-induced elevation in NMDA receptor expression. 89 In contrast, activation of the receptor in the prefrontal cortex reduced anxiety-like behaviour, whereas its knockdown was anxiogenic, 83 suggesting region-dependent effect of the EphB2 receptor in anxiety responses. Autism Autism represents a group of neurodevelopmental conditions characterized by alterations in social interaction and communication, behaviour, learning, and memory. 90 Typically with an onset in childhood, diagnosed individuals fall under high-functioning and low-functioning categories. 90 While there are known genetic factors, most cases of autism are idiopathic with no known cause. This, in association with the diversity of phenotypes across the spectrum, and the high prevalence of comorbidities, makes understanding the causal factors of autism challenging. There is, however, emerging evidence implicating the Eph-ephrin system in autism. De novo missense variants in the EPHA1 gene in autism have been reported 91 , 92 and EPHA3, EPHA4, EPHA6, EPHB2, and EPHB6 have also been identified as candidate risk genes, 93 – 95 although the EPHA4 gene was evaluated only in females. In postmortem analysis of brain tissue from autistic individuals, mRNA and protein expression of the axon guidance proteins ephrin A4, ephrin B3, plexin A4, and roundabout 2 and 3 were each found to be lower in the anterior cingulate cortex compared to healthy controls. 96 Valproic acid (VPA) exposure during pregnancy has been identified as a risk factor in the development of autism in the offspring, and following prenatal VPA exposure in mice, there are compartment-specific striatal alterations in EphA4 receptor and ephrin A5 expression. 97 It was posited that VPA may interfere with ephrin A5-EphA4 receptor-mediated repulsion between striosomal and matrix neurons leading to their intermingling; 97 however, this would be likely an indirect effect as VPA could potentially affect many targets. In triple functional domain ( TRIO ) KO mice, a gene associated with autism, epileptic encephalopathy, and intellectual deficiency, ephrin A2-EphA4 receptor-mediated RhoA signalling is disrupted. 98 The loss of the protein TRIO, which is a downstream effector of ephrin A2-mediated EphA4 receptor activation, resulted in deficiencies in cortical GABAergic interneuron radial migration such as premature radial migration, aberrant cortical plate entry, and deficiencies in cytoskeletal dynamics. 98 Alterations in myelination have also been observed in autistic children. 99 Although a link between the reported myelination alterations in autism and Eph-ephrin functions has not been studied, it is worthy of investigation as the EphA4 receptor has been implicated in persistent myelination deficits in rodent stress models, notably in a neuroinflammatory LPS model. 81 Haploinsufficiency of the EphA7 receptor gene has been shown to accompany a neurodevelopmental disability phenotype in humans. 100 Variants in the ASH1L gene, which encodes for a histone methyltransferase and has been implicated in the regulation of EphA7 receptor gene expression, 101 are known risk factors for autism. 102 , 103 In a seminal study in mice by Yan et al., 101 forebrain ASH1L expression deficits in neurons decreased synaptic pruning and induced autism-like social deficits and anxiety-like behaviour. Although histone methyltransferases have many targets, EphA7 receptor mRNA expression was reduced in these mice in several brain regions via the epigenetic H3k27me3 modification of histone H3. 101 Furthermore, in forebrain ASH1L haploinsufficient mice, activation of the EphA7 receptor by ephrin-A5 promoted synaptic pruning and alleviated autism-related behavioural deficits. 101 Ephrin A2/3 double KO mice have also been suggested to have potential as a rodent model to study autism as these mice exhibit a behavioural autism-like phenotype, engaging in repetitive and self-centered behaviours, decreased sociality, and anxiety-like behaviour. 104 Impaired inhibition and inhibitory synapse pathologies and parvalbumin interneuron hypofunction are thought to underlie the hyperexcitability observed in autism. 105 , 106 In mice, genetic deletion of the EphB2 receptor from hippocampal parvalbumin-expressing interneurons during early postnatal development enhanced structural and functional connectivity between parvalbumin expressing interneurons and pyramidal neurons, with the strength of connectivity being dependent upon expression of astrocytic ephrin B1. 107 Conversely, the loss of astrocytic ephrin B1 reduced connectivity, and promoted the development of autism-like behaviours such as anxiety, social deficits, and repetitive behaviours. 107 Finally, EphB6 receptor deletion was shown to induce autism-like behaviour in mice, such as increased self-grooming, and social deficits. 108 Interestingly, transplantation of fecal microbiota from EphB6 receptor KO mice to wildtype mice produced autism-like behaviours, while transplantation of fecal microbiota from wildtype mice ameliorated these behaviours in the EphB6 receptor KO mice. 108 The authors suggested that loss of the EphB6 receptor might dysregulate the interaction between Eph families and junction proteins leading to increased intestinal mucosal permeability and gut microbial dysbiosis in mice as they found gut microbial dysbiosis was required for autism-like behaviour in EphB6-deficient mice. 108 EphB class receptor signalling has also been shown to be downregulated in both the prefrontal cortex and hippocampus under inflammatory stress from maternal immune activation in rats. 109 As maternal immune activation is a known risk factor for autism, 110 this provides an additional mechanism linking the Eph-ephrin system to autism. While a variety of Eph receptors have been implicated in autism, studies are sporadic with only a handful mechanistically linking specific Eph receptors to autism-like behaviours in translational studies. However, given these findings and the importance of the Eph-ephrin system in neurodevelopment, a more in depth examination of the role of specific ephrins and Eph receptors in autism is warranted. Schizophrenia Schizophrenia is a heterogeneous neurodevelopmental disorder characterized by both positive and negative symptoms, as well as cognitive impairments. Underlying the cognitive deficits of schizophrenia are disruptions to synaptic plasticity, 111 decreases in dendritic spine densities, 112 and increased neuroinflammation. 113 Together these contribute to aberrant functional connectivity between brain regions. 114 Studies have identified genetic risk factors for schizophrenia that are related to the Eph-ephrin system. In Chinese Zhuang and Han populations, two single nucleotide polymorphisms rs11918092 and rs9520087 in the EPHB1 and EPHB2 genes, respectively, were linked to the psychopathological symptoms of schizophrenia. 115 Similarly, in both European and Han Chinese populations, the EFNB2 gene, encoding ephrin B2, was identified as a schizophrenia risk gene in several studies. 116 – 118 The MIR137 gene, which encodes for a post-transcriptional regulator of EFNB2 , has been shown to contribute to schizophrenia risk 118 , 119 with detection of miR-137 levels in peripheral blood found to be a consistent diagnostic tool for early-onset schizophrenia. 116 Another study found that MIR137 expression was positively corelated with lateral ventricle size and inversely with corpus callosum volume in human clinical data, both of which are consistent with schizophrenia pathophysiology. 120 Furthermore, the corpus callosum:lateral ventricle volume ratio in these individuals was significantly associated with ephrin pathway gene expression. 120 It should be noted, however, mir-137 would have numerous targets and studies have not yet examined whether ephrin B2 mRNA is altered in schizophrenia brain. Phosphoprotein and protein expression analysis in schizophrenia patient corpus callosum, however, did identify alterations in the expression of proteins involved in canonical ephrin B signalling, highlighting a potential link between EphB2 or other EphB receptor signalling and schizophrenia. 121 Downregulation of the gene encoding opioid-binding protein/cell adhesion molecule, OPCML, has also been reported in schizophrenia. 122 OPCML is a synaptic membrane protein highly expressed in the brain during fetal development and plays a pivotal role in dendritic spine formation. 122 Targeted deletion of OPCML in the hippocampus of mice resulted in fewer numbers of mature dendritic spines by disrupting F-actin through decreased cofilin phosphorylation, leading to impaired cognitive and sensorimotor function. 122 Evidence suggests that OPCML interacts with the EphB2 receptor to regulate the EphB2-cofilin pathway, as EphB2 receptor phosphorylation was significantly lower in hippocampal neurons lacking OPCML, coincident with weaker EphB2–ephrinA5 interactions and subsequent disruptions to EphB2 receptor signalling pathways. 122 The Eph-ephrin system has also been implicated in glutamatergic signalling alterations in schizophrenia. Prefrontal cortical NMDA receptor hypofunction has been heavily implicated in schizophrenia pathology, 123 and treatment of human brain slices with the NMDA receptor antagonist MK-801 induced changes to several proteins involved in Eph-ephrin signalling, such as decreases in Rac, RhoA, and Rho GTPase signalling. 123 Coadministration of haloperidol and clozapine with MK-801 was able to restore signalling protein levels, counteracting the effects of MK-801. 123 Circulating NMDA receptor autoantibodies have been shown to be present in schizophrenia patients that exhibit psychosis. 124 In human embryonic kidney cells, it was found that NMDA receptor autoantibodies led to increased GluN2A-NMDA receptor surface expression in the presynapse. 124 Furthermore, the autoantibodies disorganized EphB2 receptor expression in the synapse and reduced receptor clustering; however, whether this was a direct or indirect effect of the autoantibodies is unknown. Regardless, this may be a notable finding given the aforementioned role of the EphB2 receptor to enhance NMDA receptor activation and promote LTP. 11 , 44 , 46 Indeed, it was also determined that the presence of autoantibodies in hippocampal neurons in culture impaired glutamatergic LTP following cLTP stimulation. 124 The EphA4 receptor and ephrin-A3 have been implicated in dendritic pruning, 51 , 125 a known characteristic of schizophrenia, suggesting that these proteins may also be involved in schizophrenia pathology. This is supported by a study using astrocytes differentiated from human induced pluripotent stem cells (iPSCs) from monozygotic twins, one of which developed schizophrenia. 126 Whereas all siblings with schizophrenia showed elevated EPHA5 gene expression, only the female siblings with schizophrenia had elevated EPHA3 gene expression. 126 Furthermore, GO enrichment analysis showed enrichment in ephrin A and RhoA signalling in the siblings that had schizophrenia compared to the healthy siblings. 126 Disrupted-in-schizophrenia1 (DISC1) is a protein previously implicated in schizophrenia. 127 A quantitative proteomic study in the dorsal striatum of transgenic rats expressing human DISC1 showed elevated EphA6 receptor expression and significant alterations in downstream Eph receptor signalling. 127 Select EphA and EphB receptors have been identified as potential schizophrenia risk genes; however, translational studies remain associative. However, given the known role of EphA receptors to promote dendritic retraction, and EphB receptors to induce dendritic growth and promote LTP, it is logical that if these receptors were mechanistically involved in schizophrenia, prefrontal cortical EphA function would be enhanced and/or EphB function would be suppressed. It is also noteworthy that inflammation and enhanced vascular permeability have also been proposed as a pathogenic mechanism of schizophrenia, 113 , 128 , 129 providing another potential link of the Eph-ephrin system to schizophrenia pathology that has yet to be explored. Future research directions and challenges Given that the Eph receptor family is the largest family of tyrosine receptor kinases, it is surprising that there is such a dearth of research on their functional role in brain beyond neurodevelopment. Beyond a handful of reports, most of which are gene association studies, human data are limited. More translational and clinical research focusing on the function of ephrins and Eph receptors in healthy individuals of all ages, in those who exhibit neurodiversity, as well as those who have a neuropsychiatric or neurodevelopmental disorder would not only help expand our fundamental understanding of their functional importance in the brain but also identify their potential value as therapeutic targets. However, like many other receptor targets, Eph receptors are widely expressed, and so future in vivo studies examining their role in brain disorders should be diligent in characterizing adverse events. Both the ephrin ligands and their respective receptors initiate reverse and forward signalling cascades, respectively, upon binding, and each can be manipulated through various approaches to determine their functional role. In translational studies, the use of transgenic KO mice or pharmacogenetic manipulation, for example, are often two such approaches that can be used effectively to study both the ephrins and Eph receptors. Pharmacological approaches remain a challenge as the availability of receptor selective agonists and antagonists are limited. For those drugs that are available, characterization remains restricted to in vitro studies that may be associated, in part, to high purchase costs. There are lower cost pharmacological options that are commercially available, for example, select ephrins; however, these protein agonists are non-selective with promiscuous binding. In 2018, Gomez-Solar et al. 130 developed selective inhibiting and activating peptides for the human EphA2 receptor. While at this time peptides are more cost effective, their inability to cross the BBB in many cases can be a limiting factor, and validation of their specificity in rodent models remains to be determined. As a result of these pharmacological limitations, studies evaluating ephrin and Eph receptor function generally combine pharmacological approaches with other methodologies to better ensure specificity of the characterized response. There are many ephrins and Eph receptors; however, most have not been studied in in vivo models in later development and are therefore wide open to functional exploration. It should also be highlighted that many of the existing studies linking the Eph-ephrin system to autism or to brain disorders are associative, although mechanistic roles for the EphA4 and EphB2 receptor in mediating depression-like behaviour in stress models have been demonstrated. 80 , 83 With the EphA4 and EphB2 receptors demonstrating an important and often opposing role in synaptic function through the modulation of dendritic spines, both are promising targets in situations where altered functional connectivity are core features, such as is seen in autism or schizophrenia. The EphA2 receptor is also worth highlighting as having therapeutic promise. Although not well studied in brain, likely due to its overall low expression levels comparative to other Eph receptors, these receptors are highly sensitive to inflammatory insult. Expressed in endothelial cells, the EphA2 receptor is activated by ephrin A1 under inflammatory conditions to promote vascular permeability through the regulation of tight and adherens junctions ( Fig. 1 ). Furthermore, the EphA2 receptor itself promotes inflammatory signalling. This suggests that pharmacological EphA2 receptor inhibition would not only be therapeutic under conditions of inflammation, as is seen in most brain disorders, negative effects of receptor inhibition would presumably be minimal due to its relatively low expression outside the vasculature and its specific induction in pathogenic states. Overall, given their important role in numerous processes associated with brain function, namely synaptic function, inflammation, and vascular permeability, Eph receptors represent attractive targets for therapeutic intervention in brain disorders with extensive in vivo study still required. Conclusion The Eph-ephrin system encompasses a wide range of functions in both developmental and adult brain physiology. While traditionally understood in the context of development and cancer, there is emerging evidence implicating the Eph-ephrin system in a myriad of brain disorders. While still in its infancy, investigation into the Eph-ephrin system in brain disorders stands to further the understanding of the specific cellular mechanisms that underlie brain disorder pathology. In this regard, a mechanistic link between the Eph-ephrin system and synaptic plasticity, inflammation, and vascular permeability inherent in many brain disorders is perhaps the most critical; however, further investigation is yet needed. Acknowledgements This work was supported by a grant (to MLP) from the Canadian Institutes of Health Research (#450277). We would like to acknowledge the land in Ontario, Canada, on which this research was performed, the ancestral lands of the Attawandaron people, and the treaty lands and territory of the Mississaugas of the Credit First Nation. We also offer our respect to all of the First Nations, Inuit, and Métis peoples, acknowledging their spirituality, traditional knowledge, and cultural diversity. We offer our gratitude for their environmental stewardship from time immemorial. Data availability Not applicable. Author contributions Conceptualization: AB, MLP Funding acquisition: MLP Investigation: AB Project administration: MLP Supervision: MLP Writing – original draft: AB, JDM Writing – review & editing: JDM, MLP References (1). Hirai H., Maru Y., Hagiwara K., Nishida J., Takaku F.. Science, 1987, 238, 1717. doi: 10.1126/science.2825356. [ DOI ] [ PubMed ] [ Google Scholar ] (2). Kania A., Klein R.. Nat. Rev. Mol. Cell Biol. 2016, 17, 240. doi: 10.1038/nrm.2015.16. [ DOI ] [ PubMed ] [ Google Scholar ] (3). Lackmann M., Boyd A.W.. Sci. Signal, 2008, 1. doi: 10.1126/stke.115re2. [ DOI ] [ Google Scholar ] (4). Gale N.W., Holland S.J., Valenzuela D.M., Flenniken A., Pan L.i, Ryan T.E., et al. , Neuron, 1996, 17, 9. doi: 10.1016/S0896-6273(00)80276-7. [ DOI ] [ PubMed ] [ Google Scholar ] (5). Himanen J.P., Yermekbayeva L., Janes P.W., Walker J.R., Xu K., Atapattu L., et al. Proc. Natl. Acad. Sci. 2010, 107, 10860. doi: 10.1073/pnas.1004148107. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (6). Pasquale E. B. Cell, 2008, 133, 38. doi: 10.1016/j.cell.2008.03.011. [ DOI ] [ PubMed ] [ Google Scholar ] (7). Himanen J.-P., Chumley M.J., Lackmann M., Li C., Barton W.A., Jeffrey P.D., Vearing C., et al. Nat. Neurosci. 2004, 7, 501. doi: 10.1038/nn1237. [ DOI ] [ PubMed ] [ Google Scholar ] (8). Zisch A.H., Kalo M.S., Chong L.D., Pasquale E.B.. Oncogene, 1998, 16, 2657. doi: 10.1038/sj.onc.1201823. [ DOI ] [ PubMed ] [ Google Scholar ] (9). Murai K.K., Pasquale E.B.. J. Cell Sci. 2003, 116, 2823. doi: 10.1242/jcs.00625. [ DOI ] [ PubMed ] [ Google Scholar ] (10). Himanen J.-P., Nikolov D.B.. Trends Neurosci. 2003, 26, 46. doi: 10.1016/S0166-2236(02)00005-X. [ DOI ] [ PubMed ] [ Google Scholar ] (11). Dalva M.B., Takasu M.A., Lin M.Z., Shamah S.M., Hu L., Gale N.W., et al. Cell, 2000, 103, 945. doi: 10.1016/S0092-8674(00)00197-5. [ DOI ] [ PubMed ] [ Google Scholar ] (12). Seiradake E., Harlos K., Sutton G., Aricescu A.R., Jones E.Y.. Nat. Struct. Mol. Biol. 2010, 17, 398. doi: 10.1038/nsmb.1782. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (13). Qin H., Shi J., Noberini R., Pasquale E.B., Song J.. J. Biol. Chem. 2008, 283, 29473. doi: 10.1074/jbc.M804114200. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (14). Mason E.O., Goldgur Y., Robev D., Freywald A., Nikolov D.B., Himanen J.P.. PLoS One, 2021, 16, e0247335. doi: 10.1371/journal.pone.0247335. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (15). Himanen J.-P., Rajashankar K.R., Lackmann M., Cowan C.A., Henkemeyer M., Nikolov D.B.. Nature, 2001, 414, 933. doi: 10.1038/414933a. [ DOI ] [ PubMed ] [ Google Scholar ] (16). Seiradake E., Schaupp A., Del Toro Ruiz D., Kaufmann R., Mitakidis N., Harlos K., et al. Nat. Struct. Mol. Biol. 2013, 20, 958. doi: 10.1038/nsmb.2617. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (17). Bundesen L.Q., Scheel T.A., Bregman B.S., Kromer L.F.. J. Neurosci. 2003, 23, 7789. doi: 10.1523/JNEUROSCI.23-21-07789.2003. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (18). Tanaka M., Kamata R., Sakai R.. EMBO J. 2005, 24, 3700. doi: 10.1038/sj.emboj.7600831. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (19). Davis S., Gale N.W., Aldrich T.H., Maisonpierre P.C., Lhotak V., Pawson T., et al. Science, 1994, 266, 816. doi: 10.1126/science.7973638. [ DOI ] [ PubMed ] [ Google Scholar ] (20). Wimmer-Kleikamp S.H., Janes P.W., Squire A., Bastiaens P.I.H., Lackmann M.. J. Cell Biol. 2004, 164, 661. doi: 10.1083/jcb.200312001. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (21). Egea J., Nissen U.V., Dufour A., Sahin M., Greer P., et al. Neuron, 2005, 47, 515. doi: 10.1016/j.neuron.2005.06.029. [ DOI ] [ PubMed ] [ Google Scholar ] (22). Carvalho R.F., Beutler M., Marler K.J.M., Knöll B., Becker-Barroso E., Heintzmann R., et al. Nat. Neurosci. 2006, 9, 322. doi: 10.1038/nn1655. [ DOI ] [ PubMed ] [ Google Scholar ] (23). Chin-Sang I.D., Moseley S.L., Ding M., Harrington R.J., George S.E., Chisholm A.D.. Development, 2002, 129, 5499. doi: 10.1242/dev.00122. [ DOI ] [ PubMed ] [ Google Scholar ] (24). Lisabeth E.M., Falivelli G., Pasquale E.B.. Cold Spring Harb. Perspect. Biol. 2013, 5, a009159. doi: 10.1101/cshperspect.a009159. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (25). Pasquale E. B. Nat. Rev. Cancer, 2010, 10, 165. doi: 10.1038/nrc2806. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (26). Jørgensen C., Sherman A., Chen G.I., Pasculescu A., Poliakov A., Hsiung M., et al. Science 2009, 326, 1502. [ DOI ] [ PubMed ] [ Google Scholar ] (27). Sahin M., Greer P.L., Lin M.Z., Poucher H., Eberhart J., Schmidt S., et al. Neuron, 2005, 46, 191. doi: 10.1016/j.neuron.2005.01.030. [ DOI ] [ PubMed ] [ Google Scholar ] (28). Hunter S.G., Zhuang G., Brantley-Sieders D., Swat W., Cowan C.W., Chen J.. Mol. Cell. Biol. 2006, 26, 4830. doi: 10.1128/MCB.02215-05. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (29). Beg A.A., Sommer J.E., Martin J.H., Scheiffele P.. Neuron, 2007, 55, 768. doi: 10.1016/j.neuron.2007.07.036. [ DOI ] [ PubMed ] [ Google Scholar ] (30). Liang L.-Y., Patel O., Janes P.W., Murphy J.M., Lucet I.S.. Oncogene, 2019, 38, 6567. doi: 10.1038/s41388-019-0931-2. [ DOI ] [ PubMed ] [ Google Scholar ] (31). Miao H., Li D.Q., Mukherjee A., Guo H., Petty A., Cutter J., et al. Cancer Cell, 2009, 16, 9. doi: 10.1016/j.ccr.2009.04.009. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (32). Lim Y.-S., Mclaughlin T., Sung T.-C., Santiago A., Lee K.-F., O'Leary D.D.M.. Neuron, 2008, 59, 746. doi: 10.1016/j.neuron.2008.07.032. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (33). Marler K.J.M., Becker-Barroso E., Martínez A., Llovera M., Wentzel C., Poopalasundaram S., et al. J. Neurosci. 2008, 28, 12700. doi: 10.1523/JNEUROSCI.1915-08.2008. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (34). Holmberg J., Armulik A., Senti K.-A., Edoff K., Spalding K., Momma S., et al. Genes Dev. 2005, 19, 462. doi: 10.1101/gad.326905. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (35). Carmona M.A., Murai K.K., Wang L., Roberts A.J., Pasquale E.B.. Proc. Natl. Acad. Sci. 2009, 106, 12524. doi: 10.1073/pnas.0903328106. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (36). Palmer A., Zimmer M., Erdmann K.S., Eulenburg V., Porthin A., Heumann R., et al. Mol. Cell, 2002, 9, 725. doi: 10.1016/S1097-2765(02)00488-4. [ DOI ] [ PubMed ] [ Google Scholar ] (37). Cowan C. A., Henkemeyer M.. Nature, 2001, 413, 174. doi: 10.1038/35093123. [ DOI ] [ PubMed ] [ Google Scholar ] (38). Segura I., Essmann C.L., Weinges S., Acker-Palmer A.. Nat. Neurosci. 2007, 10, 301. doi: 10.1038/nn1858. [ DOI ] [ PubMed ] [ Google Scholar ] (39). Qiu R., Wang J., Tsark W., Lu Q.. Stem Cells, 2010, 28, 1602. doi: 10.1002/stem.478. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (40). Duan C., Hare M.M., Staring M., Deligiannidis K.M.. Int. Rev. Psychiatry, 2019, 31, 264. doi: 10.1080/09540261.2018.1527759. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (41). Weinberger D. R. Schizophr. Bull. 2017, 43, 1164. doi: 10.1093/schbul/sbx118. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (42). Yang G., Shcheglovitov A.. Dev. Dynamics 2020, 249, 6. doi: 10.1002/dvdy.100. [ DOI ] [ Google Scholar ] (43). Leicht G., Kirsch V., Giegling I., Karch S., Hantschk I., Möller H.-J., et al. Biol. Psychiatry, 2010, 67, 224. doi: 10.1016/j.biopsych.2009.07.033. [ DOI ] [ PubMed ] [ Google Scholar ] (44). Contractor A., Rogers C., Maron C., Henkemeyer M., Swanson G.T., Heinemann S.F.. Science 2002, 296, 1864. [ DOI ] [ PubMed ] [ Google Scholar ] (45). Essmann C.L., Martinez E., Geiger J.C., Zimmer M., Traut M.H., Stein V., et al. Nat. Neurosci. 2008, 11, 1035. doi: 10.1038/nn.2171. [ DOI ] [ PubMed ] [ Google Scholar ] (46). Henderson J.T., Georgiou J., Jia Z., Robertson J., Elowe S., Roder J.C., et al. Neuron, 2001, 32, 1041. doi: 10.1016/S0896-6273(01)00553-0. [ DOI ] [ PubMed ] [ Google Scholar ] (47). Henkemeyer M., Itkis O.S., Ngo M., Hickmott P.W., Ethell I.M.. J. Cell Biol. 2003, 163, 1313. doi: 10.1083/jcb.200306033. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (48). Moeller M.L., Shi Y., Reichardt L.F., Ethell I.M.. J. Biol. Chem. 2006, 281, 1587. doi: 10.1074/jbc.M511756200. [ DOI ] [ PubMed ] [ Google Scholar ] (49). Tolias K.F., Bikoff J.B., Kane C.G., Tolias C.S., Hu L., Greenberg M.E.. Proc. Natl. Acad. Sci. 2007, 104, 7265. doi: 10.1073/pnas.0702044104. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (50). Planagumà J., Haselmann H., Mannara F., Petit‐Pedrol M., Grünewald B., Aguilar E., et al. Ann. Neurol. 2016, 80, 388. doi: 10.1002/ana.24721. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (51). Murai K.K., Nguyen L.N., Irie F., Yamaguchi Y., Pasquale E.B.. Nat. Neurosci. 2003, 6, 153. doi: 10.1038/nn994. [ DOI ] [ PubMed ] [ Google Scholar ] (52). Fu A.K.Y., Hung K.-W., Huang H., Gu S., Shen Y., Cheng E.Y.L., et al. Proc. Natl. Acad. Sci. 2014, 111, 9959. doi: 10.1073/pnas.1405803111. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (53). Fu W.-Y., Chen Y., Sahin M., Zhao X.-S., Shi L., Bikoff J.B., et al. Nat. Neurosci. 2007, 10, 67. doi: 10.1038/nn1811. [ DOI ] [ PubMed ] [ Google Scholar ] (54). Zhang J.-C., Yao W., Qu Y., Nakamura M., Dong C., Yang C., et al. Sci. Rep. 2017, 7, 7133. doi: 10.1038/s41598-017-07325-2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (55). Filosa A., Paixão S., Honsek S.D., Carmona M.A., Becker L., Feddersen B., et al. Nat. Neurosci. 2009, 12, 1285. doi: 10.1038/nn.2394. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (56). Gerlai R., Shinsky N., Shih A., Williams P., Winer J., Armanini M., et al. J. Neurosci. 1999, 19, 9538. doi: 10.1523/JNEUROSCI.19-21-09538.1999. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (57). Gao W.-Q., Shinsky N., Armanini M.P., Moran P., Zheng J.L., Mendoza-Ramirez J.-L., et al. Mol. Cell. Neurosci. 1998, 11, 247. doi: 10.1006/mcne.1998.0696. [ DOI ] [ PubMed ] [ Google Scholar ] (58). Zhao B.O, Yin Q., Fei Y., Zhu J., Qiu Y., Fang W., et al. Arch. Physiol. Biochem. 2022, 128, 1579. doi: 10.1080/13813455.2020.1784952. [ DOI ] [ PubMed ] [ Google Scholar ] (59). Ouellette J., Lacoste B.. Front. Aging Neurosci. 2021, 13, 749026. doi: 10.3389/fnagi.2021.749026. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (60). Binder L.B., Menegatti Bevilacqua L., Gro Lorentzen Thomassen F., Lebel M., Jensen B.A.H., Menard C.. J. Neurochem. 2025, 169, e70282. doi: 10.1111/jnc.70282. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (61). Coulthard M.G., Morgan M., Woodruff T.M., Arumugam T.V., Taylor S.M., Carpenter T.C., et al. Am. J. Pathol. 2012, 181, 1493. doi: 10.1016/j.ajpath.2012.06.043. [ DOI ] [ PubMed ] [ Google Scholar ] (62). Chen F., Liu Z., Peng W., Gao Z., Ouyang H., Yan T., et al. Exp. Ther. Med. 2018, 16, 2651. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (63). Ménard C., Pfau M.L., Hodes G.E., Russo S.J.. Neuropsychopharmacology 2017, 42, 62. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (64). Zhao Y., Xu J.. Inflammation, 2020, 43, 1476. doi: 10.1007/s10753-020-01225-w. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (65). Feng S., Zou L., Wang H., He R., Liu K., Zhu H.. Molecules 2018, 23, 2371. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (66). Han X., Wu Y., Zhuang Y., Zhang J.. Allergol. Immunopathol.  2022, 50, 85. doi: 10.15586/aei.v50i3.569. [ DOI ] [ Google Scholar ] (67). Beamish I.V., Hinck L., Kennedy T.E.. Cold Spring Harb. Perspect. Biol. 2018, 10, a029165. doi: 10.1101/cshperspect.a029165. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (68). Tanaka M., Kamata R., Sakai R.. J. Biol. Chem. 2005, 280, 42375. doi: 10.1074/jbc.M503786200. [ DOI ] [ PubMed ] [ Google Scholar ] (69). Fang W.B., Ireton R.´C., Zhuang G., Takahashi T., Reynolds A.l, Chen J.. J. Cell Sci. 2008, 121, 358. doi: 10.1242/jcs.017145. [ DOI ] [ PubMed ] [ Google Scholar ] (70). Darling T.K., Mimche P.N., Bray C., Umaru B., Brady L.M., Stone C., et al. PLoS Pathog. 2020, 16, e1008261. doi: 10.1371/journal.ppat.1008261. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (71). Al-Sadi R. Front. Biosci. 2009, 14, 2765. doi: 10.2741/3413. [ DOI ] [ Google Scholar ] (72). Stone K. P., Kastin A. J., Pan W.. Cell. Physiol. Biochem. 2011, 28, 115–124. doi: 10.1159/000331720. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (73). Ma T.Y., Iwamoto G.K., Hoa N.T., Akotia V., Pedram A., Boivin M.A., et al. Am. J. Physiol. Gastrointestinal Liver Physiol. 2004, 286, G367. doi: 10.1152/ajpgi.00173.2003. [ DOI ] [ Google Scholar ] (74). Ivanov A.I., Steiner A.A., Scheck A.C., Romanovsky A.A.. Physiol. Genom. 2005, 21, 152. doi: 10.1152/physiolgenomics.00043.2004. [ DOI ] [ Google Scholar ] (75). Zajkowska Z., Walsh A., Zonca V., Gullett N., Pedersen G.A., Kieling C., et al. J. Psychiatr. Res. 2021, 138, 163. doi: 10.1016/j.jpsychires.2021.04.003. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (76). Asim M., Wang H., Waris A.. Neuropeptides, 2023, 98, 102322. doi: 10.1016/j.npep.2023.102322. [ DOI ] [ PubMed ] [ Google Scholar ] (77). Duman R. S., Aghajanian G. K.. Science, 2012, 338, 68. doi: 10.1126/science.1222939. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (78). Yin Y., Ju T., Zeng D., Duan F., Zhu Y., Liu J., et al. Pharmacol. Res. 2024, 207, 107322. doi: 10.1016/j.phrs.2024.107322. [ DOI ] [ PubMed ] [ Google Scholar ] (79). Welcome M. O. Inflammopharmacology, 2020, 28, 643. doi: 10.1007/s10787-020-00712-8. [ DOI ] [ PubMed ] [ Google Scholar ] (80). Li Y., Wang H., Wang X., Liu Z., Wan Q., Wang G.. Neurosci. Lett. 2014, 566, 292. doi: 10.1016/j.neulet.2014.03.008. [ DOI ] [ PubMed ] [ Google Scholar ] (81). Li Y., Su P., Chen Y., Nie J., Yuan T.F., Wong A.H.C., et al. J. Clin. Invest. 2022, 132, e152187. doi: 10.1172/JCI152187. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (82). Zhen L., Shao T., Luria V., Li G., Li Z., Xu Y., Zhao X.. Front. Pharmacol. 2018, 9. doi: 10.3389/fphar.2018.00862. [ DOI ] [ Google Scholar ] (83). Zhang R.-X., Han Y., Chen C., Xu L.-Z., Li J.-L., Chen N.A, et al. Neuropsychopharmacology, 2016, 41, 2541. doi: 10.1038/npp.2016.58. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (84). Wu Y.U, Wei Z., Li Y., Wei C., Li Y., Cheng P., et al. Front. Neurosci. 2019, 13, 1359. doi: 10.3389/fnins.2019.01359. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (85). Guo H., Huang Z.-L., Wang W., Zhang S.-X., Li J., Cheng K.E, et al. PROTEOMICS Clin. Appl. 2017, 11, 1700115. doi: 10.1002/prca.201700115. [ DOI ] [ Google Scholar ] (86). Attwood B.K., Bourgognon J.-M., Patel S., Mucha M., Schiavon E., Skrzypiec A.E., et al. Nature, 2011, 473, 372. doi: 10.1038/nature09938. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (87). Binder E. B. Psychoneuroendocrinology, 2009, 34, S186. doi: 10.1016/j.psyneuen.2009.05.021. [ DOI ] [ PubMed ] [ Google Scholar ] (88). Wang Q., Shelton R. C., Dwivedi Y.. J. Affect. Disord. 2018, 225, 422. doi: 10.1016/j.jad.2017.08.066. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (89). Zhang J.-T., Liu Y., Li L.-X., Li K., Chen J.-G., Wang F.. Neuropharmacology, 2020, 167, 107934. doi: 10.1016/j.neuropharm.2019.107934. [ DOI ] [ PubMed ] [ Google Scholar ] (90). Riglin L., Wootton R.E., Thapar A.K., Livingston L.A., Langley K.. Am. J. Psychiatry, 2021, 178, 752. doi: 10.1176/appi.ajp.2020.20071119. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (91). Iossifov I., O'Roak B.J., Sanders S.J., Ronemus M., Krumm N., Levy D., et al. Nature, 2014, 515, 216. doi: 10.1038/nature13908. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (92). Feliciano P., Zhou X., Astrovskaya I., Turner T.N., Wang T., Brueggeman L., et al. npj Genom. Med . 2019, 4, 19. doi: 10.1038/s41525-019-0093-8. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (93). Casey J.P., Magalhaes T., Conroy J.M., Regan R., Shah N., Anney R., et al. Hum. Genet. 2012, 131, 565. doi: 10.1007/s00439-011-1094-6. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (94). Butler M.G., Rafi S. K., Manzardo A.M.. Int. J. Mol. Sci. 2015, 16, 6464. doi: 10.3390/ijms16036464. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (95). Butler M.G., Rafi S.K., Hossain W., Stephan D.A., Manzardo A.M.. Int. J. Mol. Sci. 2015, 16, 1312. doi: 10.3390/ijms16011312. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (96). Suda S., Iwata K., Shimmura C., Kameno Y., Anitha A., Thanseem I., et al. Mol. Autism, 2011, 2, 14. doi: 10.1186/2040-2392-2-14. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (97). Kuo H.-Y., Liu F.- C.. FASEB J. 2017, 31, 4458. doi: 10.1096/fj.201700054R. [ DOI ] [ PubMed ] [ Google Scholar ] (98). Eid L., Lokmane L., Raju P.K., Tene Tadoum S.B., Jiang X., Toulouse K., et al. Mol. Psychiatry, 2025, 30, 1338. doi: 10.1038/s41380-024-02742-y. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (99). Zhou X., Deng Y.–Y., Qian L., Zhong S.–S., Zou F.–Y., Shen L.–S., et al. Neuroimage, 2025, 310, 121128. doi: 10.1016/j.neuroimage.2025.121128. [ DOI ] [ PubMed ] [ Google Scholar ] (100). Lévy J., Schell B., Nasser H., Rachid M., Ruaud L., Couque N., et al. Clin. Genet. 2021, 100, 396. [ DOI ] [ PubMed ] [ Google Scholar ] (101). Yan Y., Tian M., Li M., Zhou G., Chen Q., Xu M., et al. Neuron, 2022, 110, 1156. doi: 10.1016/j.neuron.2021.12.035e9. [ DOI ] [ PubMed ] [ Google Scholar ] (102). Satterstrom F.K., Kosmicki J.A., Wang J., Breen M.S., De Rubeis S., An J.-Y., et al. Cell, 2020, 180, 568. doi: 10.1016/j.cell.2019.12.036e23. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (103). Krumm N., Turner T.N., Baker C., Vives L., Mohajeri K., Witherspoon K., et al. Nat. Genet. 2015, 47, 582. doi: 10.1038/ng.3303. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (104). Wurzman R., Forcelli P.A., Griffey C.J., Kromer L.F.. Behav. Brain Res. 2015, 278, 115. doi: 10.1016/j.bbr.2014.09.012. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (105). Sohal V.S., Rubenstein J.L.R.. Mol. Psychiatry, 2019, 24, 1248. doi: 10.1038/s41380-019-0426-0. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (106). Tang X., Jaenisch R., Sur M.. Nat. Rev. Neurosci. 2021, 22, 290. doi: 10.1038/s41583-021-00443-x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (107). Sutley-Koury S.N., Taitano-Johnson C., Kulinich A.O., Farooq N., Wagner V.A., Robles M., et al. J. Neurosci. 2024, 44, e0154242024. doi: 10.1523/JNEUROSCI.0154-24.2024. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (108). Li Y., Luo Z.-Y.I, Hu Y.-Y., Bi Y.-W., Yang J.-M., Zou W.-J., et al. Microbiome, 2020, 8, 120. doi: 10.1186/s40168-020-00884-z. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (109). Shao Y., Cai Y., Chen T., Hao K., Luo B., Wang X., et al. Genes Brain Behav . 2023, 22, e12863. doi: 10.1111/gbb.12863. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (110). Majerczyk D., Ayad E.G., Brewton K.L., Saing P., Hart P.C.. Biosci. Rep. 2022, 42, 1. doi: 10.1042/BSR20220713. [ DOI ] [ Google Scholar ] (111). Keshri N., Nandeesha H.. Indian J. Clin. Biochem. 2023, 38, 4. doi: 10.1007/s12291-022-01068-2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (112). Copf T. Neurosci. Biobehav. Rev. 2016, 68, 946. doi: 10.1016/j.neubiorev.2016.04.008. [ DOI ] [ PubMed ] [ Google Scholar ] (113). Müller N. Schizophr. Bull. 2018, 44, 973. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (114). Sheffield J.M., Barch D.M.. Neurosci. Biobehav. Rev. 2016, 61, 108. doi: 10.1016/j.neubiorev.2015.12.007. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (115). Su L.I, Ling W., Jiang J., Hu J., Fan J., Guo X., et al. Asia-Pacific Psychiatry, 2016, 8, 306. doi: 10.1111/appy.12241. [ DOI ] [ PubMed ] [ Google Scholar ] (116). Wu S., Zhang R., Nie F., Wang X., Jiang C., Liu M., et al. EBioMedicine, 2016, 12, 133. doi: 10.1016/j.ebiom.2016.09.012. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (117). Ripke S., O'Dushlaine C., Chambert K., Moran J.L., Kähler A.K., Akterin S., et al. Nat. Genet. 2013, 45, 1150. doi: 10.1038/ng.2742. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (118). Ripke S., Neale B.M., Corvin A., Walters J.T.R., Farh K.-H., Holmans P.A.et al. Nature 2014, 511, 421–42+. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (119). Trubetskoy V., Pardiñas A. F., Qi T., Panagiotaropoulou G., Awasthi S., Bigdeli T. B., et al. Nature, 2022, 604, 502. doi: 10.1038/s41586-022-04434-5. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (120). Blokland G.A.M., Maleki N., Jovicich J., Mesholam-Gately R.I., Delisi L.E., Turner J.A., et al. Int. J. Clin. Health Psychol. 2024, 24, 100458. doi: 10.1016/j.ijchp.2024.100458. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (121). Saia-Cereda V.M., Cassoli J.S., Schmitt A., Falkai P., Martins-de-Souza D.. Schizophr. Res. 2016, 177, 70. doi: 10.1016/j.schres.2016.03.022. [ DOI ] [ PubMed ] [ Google Scholar ] (122). Zhang Z., Ye M., Li Q., You Y., Yu H., Ma Y., et al. Cell Rep. 2019, 29, 49. doi: 10.1016/j.celrep.2019.08.091e7. [ DOI ] [ PubMed ] [ Google Scholar ] (123). De Almeida V., Mendes N.D., Zuccoli G.S., Reis‐De‐Oliveira G.. J. Neurochem. 2024, 168, 238. doi: 10.1111/jnc.16059. [ DOI ] [ PubMed ] [ Google Scholar ] (124). Jézéquel J., Johansson E.M., Dupuis J.P., Rogemond V., Gréa H., Kellermayer B., et al. Nat. Commun. 2017, 8, 1791. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (125). Chen Y., Fu A. K., Ip N. Y.. Cell. Signalling, 2012, 24, 606. doi: 10.1016/j.cellsig.2011.11.016. [ DOI ] [ PubMed ] [ Google Scholar ] (126). Koskuvi M., Lehtonen Š., Trontti K., Keuters M., Wu Y.‐C., Koivisto H., et al. Glia, 2022, 70, 650. doi: 10.1002/glia.24131. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (127). Sialana F. J., Wang A.L., Fazari B., Kristofova M., Smidak R., Trossbach S. V., et al. Front. Mol. Neurosci. 2018, 11, 26. doi: 10.3389/fnmol.2018.00026. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] (128). Casas B.S., Vitória G., Prieto C.P., Casas M., Chacón C., Uhrig M., et al. Mol. Psychiatry, 2022, 27, 3708. doi: 10.1038/s41380-022-01653-0. [ DOI ] [ PubMed ] [ Google Scholar ] (129). Puvogel S., Palma V., Sommer I.E.C.. Curr. Opin. Psychiatry, 2022, 35, 146. doi: 10.1097/YCO.0000000000000789. [ DOI ] [ PubMed ] [ Google Scholar ] (130). Gomez-Soler M., Petersen Gehring M., Lechtenberg B.C., Zapata-Mercado E., Hristova K., Pasquale E.B.. J. Biol. Chem. 2019, 294, 8791. doi: 10.1074/jbc.RA119.008213. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Data Availability Statement Not applicable. 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