Fibroblast growth factor receptor 1: Bridge to understanding mental disorders

Abstract

Fibroblast growth factor receptor 1 (FGFR1) is emerging as a central molecular player in the pathophysiology of major mental disorders. This review synthesizes evidence outlining its multifaceted roles, which extend from fundamental neurodevelopmental processes and the regulation of synaptic plasticity to novel signaling paradigms such as the formation of heteroreceptor complexes with specific G protein-coupled receptors and mediating neuron-glia communication. We detail how dysregulation of FGFR1 signaling is implicated in disorders including schizophrenia and depression. The accumulated preclinical and clinical findings position FGFR1 not only as a critical factor in disease mechanisms but also as a potential and pharmacologically tractable target for developing novel therapeutic strategies.

Key Words: Fibroblast growth factor receptor 1; Mental disorders; Neurodevelopment; Synaptic plasticity; Schizophrenia; Depression

Core Tip: This review establishes fibroblast growth factor receptor 1 (FGFR1) as a central signaling integrator in mental disorders, moving beyond its traditional developmental roles. We highlight novel mechanisms including dynamic heteroreceptor complex formation with neurotransmitter receptors and essential neuron-glia communication, through which FGFR1 regulates synaptic and circuit plasticity. These insights directly link FGFR1 pathway dysregulation to the pathophysiology of depression and schizophrenia, positioning it as a compelling and druggable target for next-generation therapeutics.

INTRODUCTION

Mental disorders represent a major contributor to the global burden of disease, affecting millions of individuals across all age groups and regions[1,2]. According to the Global Burden of Disease Study 2019, despite age-standardized disability-adjusted life year rates remaining relatively stable since 1990, the absolute number of disability-adjusted life years attributable to mental disorders has significantly risen because of population growth[3]. Worldwide, depressive and anxiety disorders continue to be among the leading causes of nonfatal health loss, with notable disparities in prevalence and burden between genders and across different geographical areas[4]. The impact of mental disorders extends across the lifespan, emerging early in conditions such as autism and intellectual disability and persisting into older age with disorders such as schizophrenia (SCZ) and depression[5]. Addressing this growing burden requires coordinated effort to enhance the delivery of effective prevention, treatment, and care services worldwide[6,7]. The etiology of mental disorders involves complex interactions among biological, psychological, and social factors. These include genetic vulnerability, neurobiological abnormalities, early-life trauma, chronic stress, and adverse social environments, yet the exact pathogenic pathways remain poorly understood[8,9].

Fibroblast growth factor receptor 1 (FGFR1), a receptor tyrosine kinase, serves as a “bridge” in understanding mental disorders because its involvement spans neurodevelopmental trajectories and adult plasticity, while its interactions with diverse receptors and glial cells position it at the crossroads of key pathophysiological pathways shared across disorders such as depression and SCZ. FGFR1 mediates key signaling pathways such as RAS-mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), which are essential for fundamental cellular processes including proliferation, differentiation, and survival[10]. As an important regulator, FGFR1 modulates disease-relevant processes ranging from hippocampal neurogenesis and plasticity to AKT-mammalian target of rapamycin (mTOR) signaling and synaptic function[11]. Beyond its direct involvement in specific mental conditions, FGFR1 signaling is intricately linked to broader neural and systemic functions relevant to mental health. For instance, the flavonoid chrysin can activate both tropomyosin receptor kinase B and FGFR1, upregulating endogenous ligands like brain-derived neurotrophic factor to promote neurogenesis, suggesting FGFR1 modulation may enhance neural plasticity[12,13].

Furthermore, FGFR1 variants are associated with glucose dysregulation, and its activation improves metabolic health[14,15], highlighting a potential link to the metabolic comorbidities prevalent in mood disorders. The receptor’s role extends to neuroimmune interactions and is explored in targeted central nervous system (CNS) drug delivery systems[16,17]. However, a comprehensive and integrative framework detailing how multifaceted FGFR1 signaling converges onto the pathophysiology of distinct neuropsychiatric disorders is still evolving.

This review aims to synthesize contemporary evidence to construct such an integrative framework centered on FGFR1. We systematically examine its biological functions – from nuclear signaling and heteroreceptor complex formation to its role in neuron-glia communication – and evaluate the clinical associations of aberrant FGFR1 signaling with disorders such as depression and SCZ. Finally, we discuss the therapeutic potential and challenges of targeting FGFR1, offering a fresh perspective on the biological foundations of neuropsychiatric disorders and outlining potential directions for future research (Figure 1).

Figure 1 Fibroblast growth factor receptor 1 signaling mechanisms and their roles in neuropsychiatric disorders. Canonical signaling pathways regulating cell survival, proliferation, and gene expression; nuclear signaling, involving fibroblast growth factor receptor 1 (FGFR1) translocation into the nucleus and interaction with transcription factors to promote expression of neurodifferentiation-related genes; formation of heteroreceptor complexes, such as FGFR1-5-hydroxytryptamine receptor 1A, FGFR1-D2 receptors, and FGFR1-M1R/M3R, enabling integration of growth-factor and neurotransmitter signals; and neuron-glia communication, covering central nervous system processes and peripheral nervous system events. Together, these mechanisms highlight the central role of FGFR1 in neurodevelopment, synaptic plasticity, and the pathophysiology of mental disorders such as depression and schizophrenia. AKT: Protein kinase B; CBP: CREB-binding protein; CNS: Central nervous system; D2R: D2 receptors; ERK1/2: Extracellular regulated kinase 1/2; FGF: Fibroblast growth factor; FGFR1: Fibroblast growth factor receptor 1; GLT-1: Glutamate transporter-1; MAPK: Mitogen-activated protein kinase; PI3K: Phosphatidylinositol 3-kinase; PNS: Peripheral nervous system; 5-HT: 5-hydroxytryptamine; 5-HT1A: 5-hydroxytryptamine receptor 1A.

BIOLOGICAL CHARACTERISTICS AND CNS EXPRESSION OF FGFR1

FGFR1 exhibits heterogeneous expression patterns within the CNS, contributing to its multifaceted roles in various brain functions[18]. High expression of FGFR1 is observed in neurogenic regions such as the hippocampus and subventricular zone, where it is critical in supporting adult neurogenesis and synaptic remodeling[19]. Additionally, FGFR1 is prominently expressed in cortical and limbic structures, suggesting its involvement in cognitive and emotional processing[20,21]. These distinct expression profiles underscore how the spatial distribution of FGFR1 is integral to its impact on CNS development, plasticity, and overall homeostasis.

Biological functions of FGFR1 in the CNS

FGFR1, a key member of the fibroblast growth factor (FGF) receptor family, mediates diverse biological processes through intricate signaling pathways, encompassing cell proliferation, differentiation, tissue repair, and metabolic homeostasis. Activation of FGFR1 typically initiates multiple intracellular signaling cascades, primarily the RAS-MAPK and PI3K-AKT pathways, collectively referred to as canonical signaling[22]. In CNS, the RAS-MAPK pathway is fundamental for both early and late developmental processes, controlling morphology determination, organogenesis, and synaptic plasticity[23,24]. Dysregulation of this pathway is associated with neurodevelopmental and neuropsychiatric disorders, frequently leading to cognitive deficits[25]. Mutations in genes encoding transducers within this pathway have been linked to conditions characterized by cognitive dysfunction, autism spectrum disorders, and intellectual disability[8,26].

The PI3K-AKT pathway is another crucial signaling cascade regulated by FGFR1[27,28]. This pathway is widely expressed in emotion-related brain regions and plays an essential role in neuronal proliferation, migration, and plasticity. Activation of this pathway supports neuronal survival, dendritic and axonal growth, and regulates gene expression involved in various cellular functions[29]. Dysregulation of the PI3K-AKT pathway is linked to numerous psychiatric and neurodegenerative disorders[30,31]. Furthermore, activation of FGFR1 protects hippocampal neurogenesis and ameliorates depressive-like behaviors and cognitive impairment, partially through the PI3K-AKT pathway[32]. Additionally, FGFR1 also influences neurodevelopment and neurogenesis. Oligodendrocytes, which form myelin sheaths, require FGFR1/2 signaling for oligodendrocyte precursor cell (OPC) expansion and myelin growth during development[33].

Increasing evidence indicates that RAS-MAPK and PI3K-AKT exhibit complex interactions in neural cells. For instance, sustained MAPK signaling can modulate PI3K activity through feedback phosphorylation of upstream adaptors, while AKT can phosphorylate and inhibit Raf, thereby fine-tuning MAPK output[34,35]. This bidirectional interplay determines the balance between proliferation, differentiation, and survival in neural progenitors and mature neurons[36].

Nuclear FGFR1 signaling

Beyond its classical membrane signaling, FGFR1 translocates to the nucleus and directly regulates gene expression, a process integral to neurodevelopment[21]. Live-cell imaging reveals that nuclear FGFR1 segregates into distinct kinetic populations: (1) A mobile nucleoplasmic pool; (2) A chromatin-tethered pool; and (3) An immobile matrix-associated fraction. The redistribution among these pools is dynamically controlled. For instance, transcriptional activators such as cAMP promote the shift of FGFR1 from the nuclear matrix to chromatin, enhancing its association with target genes[37]. Specifically, nerve growth factor increases the nuclear accumulation of FGFR1 by inhibiting its export. Within the nucleus, FGFR1 interacts with transcription factors such as Nurr1 and Nur77, along with co-activators including CREB-binding protein, to form transcriptional complexes that directly bind to response elements in genes encoding tyrosine hydroxylase and doublecortin[38-40]. Recent studies suggest that disruption of this FGFR1-Nurr1 interaction may contribute to dopaminergic dysfunction in mood and psychotic disorders, highlighting Nurr1 as a potential mediator of FGFR1’s neurodevelopmental effects[41,42]. Interestingly, nuclear FGFR1 has also been implicated in epigenetic regulation, where it interacts with histone-modifying enzymes to modulate chromatin accessibility and transcriptional activity[43]. Collectively, this compartmentalized regulation illustrates how nuclear FGFR1 integrates extracellular cues with transcriptional programs to orchestrate neuronal differentiation.

ROLE OF FGFR1 IN NEURODEVELOPMENT AND THE RISK OF MENTAL DISORDERS

The involvement of FGFR1 in neuropsychiatric disorders is deeply rooted in its fundamental roles during brain development and its sustained activity within the adult nervous system, FGFR1 signaling not only governs key neurodevelopmental processes such as neural stem cell proliferation, gliogenesis, and the establishment of neural circuits but also critically maintains structural and functional homeostasis in the mature brain[33]. Therefore, dysregulation of these FGFR1-mediated pathways can confer vulnerability to a spectrum of mental disorders[44].

FGFR1-anosmin-1 in oligodendrocyte myelination

FGFR1 signaling is pivotal not only in neuronal development and plasticity but also in glial lineage specification, with a particularly significant impact on oligodendrocyte biology. During both prenatal and postnatal stages, FGF signaling via FGFR1 stimulates the proliferation of neural stem cells and helps regulate cell-type proportions in various developing brain regions. Notably, members of the FGF family, especially FGF2, exert crucial effects on OPCs. Specifically, FGF2 inhibits OPC differentiation during development and impairs remyelination after chronic demyelination through FGFR1 activation; it also modulates the proliferation and migration of these cells[45,46]. The extracellular matrix glycoprotein Anosmin-1 serves as a key functional partner of FGFR1, regulating OPC proliferation, migration, and differentiation primarily through the FGFR1-ERK1/2 signaling axis[6]. In transgenic mice overexpressing human Anosmin-1, enhanced FGFR1-mediated signaling results in increased OPC proliferation, thickened myelin sheaths, elongated nodes of Ranvier, and elevated conduction velocity in the corpus callosum, underscoring the importance of the Anosmin-1-FGFR1 interaction in myelin structure and function[47]. Together, these findings demonstrate that FGFR1 – activated by canonical FGF ligands such as FGF2 and modulated by cofactors like Anosmin1 – plays a central role in oligodendroglial development and myelination[48].

FGFR1 in spinal cord injury neuroprotection

Beyond its established roles in neurodevelopment and synaptic plasticity, FGFR1 signaling also emerges as a critical mediator of neuroprotection in the context of acute CNS trauma. In a rat model of spinal cord injury (SCI), activating the FGFR1/β-klotho pathway with recombinant human FGF21 significantly alleviated secondary damage by reducing neuronal ferroptosis, attenuating mitochondrial injury, decreasing iron deposition, and promoting locomotor recovery – effects that were partially reversed by the FGFR1 inhibitor PD173074[49]. Ferroptosis, characterized by mitochondrial shrinkage, downregulation of glutathione peroxidase 4, and accumulation of lipid peroxides, has been identified as a key contributor to post-SCI pathology[50]. These findings collectively underscore the therapeutic potential of targeting the FGFR1 pathway – and its downstream regulation of ferroptosis – to mitigate secondary neuronal degeneration and support functional restoration following traumatic SCI. Although these findings highlight FGFR1’s neuroprotective role in SCI, their direct relevance to psychiatric disorders remains to be established.

FGFR1 in peripheral nerve regeneration

FGFR1 is not confined to CNS but is also expressed and functionally active in peripheral glial cells, such as Schwann cells[51]. Following sciatic nerve injury, transcripts for FGF-2 and FGFR1-3 are upregulated in Schwann cells and macrophages at the lesion site, underscoring the involvement of the FGF-2/FGFR1 axis in the cellular response to peripheral nerve damage and regeneration[52]. Specifically, after sciatic nerve crush in adult rats, FGFR1 mRNA expression increases in both proximal and distal nerve stumps and colocalizes with Schwann cells and macrophages, indicating its role in orchestrating the regenerative responses of peripheral glia[53]. More relevant to mental disorders, FGFR1 signaling modulates central neuroimmune interactions – for example, FGF21 exerts antiinflammatory effects through FGFR1 by promoting microglial M2 polarization[40]. These findings highlight FGFR1 as a multifaceted regulator that bridges peripheral nerve repair and central neuroimmune homeostasis.

FGFR1 HETERORECEPTOR COMPLEXES: A NOVEL PARADIGM FOR SIGNAL INTEGRATION

Heteroreceptor complexes represent a novel paradigm in signal integration, where FGFR1 interacts with G protein-coupled receptors (GPCRs) to form unique signaling units with distinct functional properties[54]. These complexes participate in modulating neural plasticity and neurotransmitter systems, and their dysregulation has been increasingly implicated in the pathophysiology of psychiatric disorders. Understanding the composition and dynamics of FGFR1-containing heteroreceptor complexes may thus uncover new therapeutic targets for mental illnesses[55].

FGFR1-5-hydroxytryptamine receptor 1A heteroreceptor complex

The FGFR1-5-hydroxytryptamine receptor 1A (5-HT1A) heteroreceptor complex is a prime example of such interactions, playing a pivotal role in mechanisms underlying depression and neuroplasticity[56,57]. This complex has been identified in the dorsal and median raphe nuclei of the rat midbrain and hippocampus, areas critical for serotonergic transmission and mood regulation. In genetic models of depression, such as the flinders sensitive line rats, significant functional disturbances are observed within the FGFR1-5-HT1A heteroreceptor complex. These disturbances manifest as a failure of combined agonist treatment to elicit expected antidepressant-like effects, primarily due to disrupted allosteric receptor-receptor interactions[58]. Under normal conditions, this complex is pivotal for enhancing hippocampal plasticity. Co-activation of its protomers leads to marked increases in neurite density and exerts antidepressant effects, which can help counteract hippocampal atrophy frequently observed in depression. Specifically, within midbrain raphe serotonin (5-hydroxytryptamine) neurons, synergistic allosteric interactions enhance FGFR1 signaling and are postulated to reduce the coupling of 5-HT1A autoreceptors to G-protein inwardly rectifying potassium channels – mechanisms thought to underlie the complex’s antidepressant potential[59,60]. Moreover, activation of the FGFR1 protomer within this heterocomplex restores trophic activity in forebrain networks and attenuates 5-HT1A autoreceptor-mediated inhibition. This dual action facilitates the firing of dorsal raphe 5-hydroxytryptamine neurons and enhances serotonergic transmission, processes critical for mediating antidepressant responses[54]. The specific dysfunction of this complex underscores its fundamental role in the pathophysiology of depression. However, while these preclinical models are compelling, direct evidence for the existence and dysfunction of FGFR1-5-HT1A heterocomplexes in the human depressed brain remains scarce.

Mechanistic insights into FGFR1-5-HT1A heteroreceptor complex dysfunction in depression

Further research into serotonin heteroreceptor complexes provides additional mechanistic insight into the role of FGFR1-5-HT1A complexes in depression. Studies indicate that within midbrain raphe serotonin neurons, synergistic allosteric interactions within this heterocomplex enhance FGFR1 signaling and are proposed to reduce the coupling of 5-HT1A autoreceptors to G-protein inwardly rectifying potassium channels[59,60]. This dysfunction disrupts serotonergic neuron excitability and trophic support, contributing to the neuroplasticity deficits observed in depressive disorders. Recent advancements in imaging techniques such as fluorescence resonance energy transfer and proximity ligation assays have enabled the visualization of these heterocomplexes in live cells, providing deeper insights into their dynamic behavior.

Interaction of FGFR1 with dopamine and acetylcholine receptors

Beyond serotonin receptors, FGFR1 can also form heteroreceptor complexes with other GPCRs such as dopamine D2 receptors and muscarinic acetylcholine receptors (M1R/M3R)[61]. For instance, in hippocampal neurons, the M1R-FGFR1 heterocomplex facilitates FGFR1 transactivation through allosteric mechanisms and Src kinase-mediated tyrosine phosphorylation, leading to enhanced neurite outgrowth and plasticity. The existence of M1R-FGFR1 complexes in the hippocampus and cerebral cortex has been confirmed using in situ proximity ligation assay, and their activation promotes trophic effects via Src-dependent signaling pathways[62,63].

Dynamic equilibrium of heteroreceptor complexes and psychiatric disorders

The dynamic equilibrium of heteroreceptor complexes, particularly those involving GPCRs and receptor tyrosine kinases such as FGFR1, is pivotal in brain function and is increasingly recognized in the etiology of psychiatric disorders. These heterocomplexes enable intricate signal integration and diversification, creating unique signaling mechanisms distinct from individual receptor activation[64]. For instance, interactions between FGFR1 and serotonin 5-HT1A receptors, or between dopamine D2 receptors and adenosine A2A receptors, highlight the extensive crosstalk modulating neuronal activity[11]. Dysregulation in the formation or function of such complexes can lead to imbalanced neurotransmission, contributing to conditions such as SCZ, bipolar disorder, and depression, which are often characterized by complex polygenic and multifactorial underpinnings[65]. FGFR1’s involvement in various cancers through gene amplification and mutations further demonstrates its broad impact on cellular processes, indicating the potential for systemic effects when its signaling is aberrant[10]. Therefore, understanding the dynamic modulation of these heteroreceptor complexes offers promising avenues for developing novel, more selective therapeutic strategies for neuropsychiatric conditions, potentially circumventing limitations of traditional orthosteric ligands.

FGFR1: A CRITICAL MEDIATOR OF NEURON-GLIA COMMUNICATION

Beyond its established roles in neuronal signaling and synaptic plasticity, FGFR1 serves as a vital molecular bridge facilitating bidirectional communication between neurons and glial cells across both central and peripheral nervous systems. Its expression in diverse glial populations – including astrocytes, Schwann cells, and satellite glial cells (SGCs) – enables the coordination of key processes such as glutamate homeostasis, metabolic support, and regenerative responses following injury[19].

FGFR1-mediated communication in peripheral nervous system glia

FGFR1 is expressed not only in CNS but also in peripheral glia, notably Schwann cells. Following peripheral nerve injury, the expression of FGF5 is markedly upregulated in Schwann cells, where it signals primarily through FGFR1 to enhance cell migration and adhesion – processes essential for the formation of a regenerative nerve bridge and subsequent axonal regrowth[66,67]. Intriguingly, this pro-regenerative effect of FGF5 is not mediated via the canonical ERK1/2 MAPK pathway; instead, it operates through the upregulation of the adhesion molecule N-cadherin, which promotes Schwann cell clustering and directional migration[68]. These findings underscore that FGFR1 serves as a critical molecular mediator of neuron-glia crosstalk during tissue repair, extending its functional significance beyond the CNS to encompass key regenerative events in the peripheral nervous system.

Interaction between astrocytic glutamate transporters and FGFR1

Emerging evidence underscores astrocytes as active regulators of glutamate homeostasis and emotional behavior. Pharmacological blockade or genetic knockdown of the astrocytic glutamate transporter (GLT-1) in the rodent infralimbic cortex rapidly modulates glutamatergic drive to the dorsal raphe, leading to altered serotonergic transmission and antidepressant-like effects, highlighting a crucial role of astroglial glutamate uptake in affective circuits[69,70]. While a direct molecular link between FGFR1 and GLTs remains to be fully elucidated, the presence of functional FGFR1-5-HT1A heteroreceptor complexes in hippocampal astrocytes suggests that FGFR1 signaling can modulate astroglial function and, potentially, glutamate dynamics[71]. This interaction posits FGFR1 as a potential upstream regulator of astrocytic glutamate clearance, offering a novel framework for understanding how growth factor signaling and glial excitatory amino acid transport converge to influence synaptic plasticity and behavior in mood disorders.

FGFR1 in peripheral nerve regeneration

Recent studies indicate that SGCs and sensory neurons constitute a functional unit that actively supports peripheral nerve repair. Singlecell transcriptomic analysis of injured dorsal root ganglia has established FABP7 as a specific marker of adult SGCs and demonstrated that nerve injury triggers lipid metabolic pathways and peroxisome proliferatoractivated receptor alpha signaling within SGCs – a process crucial for axonal regeneration[72]. In this setting, a distinct injuryinduced neuronal cluster (caudal intraparietal), which highly expresses regeneration-associated genes, specifically engages with SGCs through the FGF3-FGFR1 signaling axis[73,74]. Notably, FGFR1 is expressed in SGCs, and its activation may synergize with peroxisome proliferatoractivated receptor alpha dependent mechanisms to facilitate neuron – glia communication during nerve repair[72]. These findings expand the known roles of FGFR1 beyond CNS and highlight its potential as a mediator of regenerative signaling across neural compartments. The same developmental pathways that guide neural circuit formation also confer vulnerability to psychiatric disorders when dysregulated, as discussed below.

FGFR1 AND MENTAL DISORDERS

Converging evidence positions FGFR1 as a promising therapeutic target for SCZ, implicated in key pathways such as AKT-mTOR signaling and synaptic plasticity. Furthermore, significant dysregulation of FGFR1 signaling is observed in depression, particularly within hippocampal circuits critical for neurogenesis and mood regulation. Together, these findings highlight FGFR1’s involvement in neurodevelopmental and neuroplastic mechanisms underlying psychiatric conditions.

Therapeutic target for SCZ

Building on the neurodevelopmental roles outlined above, FGFR1 signaling has been increasingly implicated in the pathophysiology of major mental disorders. SCZ is a chronic psychiatric disorder characterized by positive, negative, and cognitive symptoms[75]. The AKT signaling pathway, often activated by FGFR1, has been implicated in the pathogenesis of SCZ[76]. Accumulating evidence indicates that the AKT-mTOR pathway, which is involved in long-term plasticity, is often downregulated in SCZ patients exhibiting cognitive deficits[77]. The NMDA receptor pathways, critical for synaptic plasticity and often linked to FGFR1 and PI3K-AKT signaling, are also explored as therapeutic targets for cognitive impairment in SCZ[78,79]. The integrative analysis identified FGFR1 as a candidate druggable target for SCZ. Molecular docking demonstrated strong and stable binding of known inhibitors (PD 173074, WZ-7043, lenvatinib) to FGFR1, supporting its pharmacological tractability[80]. Beyond binding affinity, FGFR1 is implicated in key pathways relevant to SCZ pathophysiology, including regulation of endothelial cell chemotaxis, phospholipase C activity, neurotrophin-receptor binding, and neuron-projection guidance – processes linked to neurodevelopmental abnormalities in SCZ[81]. Furthermore, single-cell expression analysis revealed predominant FGFR1 expression in mural cells, suggesting its potential role in cerebrovascular integrity and blood-brain barrier function, which may contribute to SCZ pathophysiology[80,82]. This hypothesis is currently based on correlational expression data and awaits functional confirmation using in vivo models and clinical translational studies. Noteworthy is the promiscuous nature of FGFR1 signaling and its vital roles in systemic physiology raise significant challenges for developing CNS-specific therapeutics without off-target effects.

FGFR1 dysregulation in depression

Depression is a highly heterogeneous syndrome with complex biological underpinnings[83]. Emerging evidence suggests that FGFR1 signaling plays a role in the context of depression. Decreased neurogenesis, neuroinflammation, and neurotransmitter imbalance are all closely related to depression, and FGFR1 is involved in regulating these processes[27]. Activation of the PI3K-AKT pathway, which is downstream of FGFR1, can protect hippocampal neurogenesis and mitigate depressive-like behaviors[84]. This pathway is a valuable target for stimulating or suppressing in psychiatric disorders.

Post-mortem studies have identified significant dysregulation of the FGFR1-FGF-2 signaling axis within the hippocampus of individuals with major depressive disorder (MDD). These investigations reveal a specific reduction in the density of FGF-2 mRNA-positive cells in the hippocampal CA4 subfield in MDD subjects compared to controls. Concurrently, an increase is present in both the percentage of FGFR1 mRNA-positive cells and the overall expression level of FGFR1 mRNA across hippocampal subregions. This pattern suggests a potential compensatory upregulation of the receptor, possibly in response to diminished availability of its ligand, FGF-2, and may contribute to the altered neuroplasticity associated with depression[85]. Recent research highlights a distinct overexpression of FGFR1, specifically within the dentate gyrus of patients with MDD, indicating its involvement in depressive pathophysiology. However, this finding is primarily derived from single post-mortem cohort studies and requires validation across multiple independent samples and species to exclude confounding factors such as agonal state, medication history, or comorbid conditions. This dysregulation of FGFR1 signaling in the hippocampus is believed to facilitate the development of depressive disorder[44].

CONCLUSION

Future research should focus on developing integrative frameworks that elucidate the precise mechanisms by which FGFR1 signaling contributes to the pathophysiology of mental disorders. This involves a deeper understanding of its interaction with other critical pathways like Notch signaling, which is implicated in autism, bipolar disorder, and SCZ, and the tropomyosin receptor kinase B/brain-derived neurotrophic factor pathway, crucial for neuronal survival, structural changes, and plasticity[86].

First, future studies should investigate how environmental factors alter FGFR1-mediated epigenetic marks and whether these changes contribute to psychiatric risk. Second, FGFR1 signaling may serve as a molecular link between the gut-brain axis and mental health, investigating whether FGFR1 mediates gut-brain communication may open new avenues for understanding the comorbidity between metabolic disorders and depression. Third, the role of FGFR1 in neuroimmune crosstalk warrants further investigation. Further insight into how FGFR1 signaling in microglia and astrocytes modulates synaptic function and behavioral outcomes could inform the development of novel anti-inflammatory therapeutic strategies. In addition, further investigation into genetic variants of FGFR1 and their impact on specific endophenotypes of mental disorders is crucial for personalized medicine approaches[31]. Examining the interplay between FGFR1, glucose dysregulation, and metabolic comorbidities, particularly in mood disorders, could unlock novel therapeutic strategies addressing both psychiatric and metabolic health. Bridging FGFR1 research with broader neuropsychiatric and metabolic health studies will be essential to provide a holistic understanding and develop effective, targeted interventions. While the findings of this study offer valuable insights, several limitations should be acknowledged. Many key conclusions – such as the role of FGFR1 in depressive-like behaviors or blood-brain barrier integrity – are derived from single animal models or in vitro experiments and lack multi-species validation. Moreover, the inference of causal relationships from correlational clinical data is complicated by potential confounding factors, including comorbidities, drug interventions, and environmental influences. Future studies should prioritize multi-model validation, longitudinal clinical assessments, and translational approaches to establish the causal involvement of FGFR1 in psychiatric pathophysiology.