The role of neuritin 1 in synaptic plasticity and sensory nerve function: A potential therapeutic target for neuronal repair

Neuritin 1 (NRN1), initially identified as an activity-dependent gene in the rat brain, has emerged as a critical regulator of synaptic plasticity and neuronal development. This review synthesizes current understanding of NRN1’s involvement in the peripheral and central nervous systems, with a focus on neuronal repair after injury in particular in sensory neurones. We discuss the evidence that NRN1 interacts with brain derived neurotrophic factor (BDNF), nerve growth factor (NGF) and modulates injury-induced plasticity, influencing local axonal mRNA translation, potassium channel function, and calcium signalling. The activity-dependent modulation of AMPA receptors and ion channel trafficking by NRN1 supports a regulatory role in synaptic efficacy and neuronal excitability. NRN1 has been shown to contribute to structural and functional recovery in neurodegenerative conditions, including Alzheimer’s disease and post-ischemic injury. The regulation of NRN1 expression and trafficking is particularly relevant in models of nerve injury and diabetic peripheral neuropathy, where its expression is reduced in pathological states, but promotes axonal regeneration and Schwann cell survival when restored. NRN1 also influences non-neuronal cell signalling pathways, including VEGF and CXCR4 expression, which are associated with inflammation and persistent pain mechanisms. The diverse effects of NRN1 suggest it serves as a molecular integrator of neurotrophic, metabolic, and injury signals, making it a promising target for therapeutic strategies aimed at enhancing neuronal repair and potentially mitigating sensory nerve dysfunction. Understanding the molecular pathways regulated by NRN1, including local translation and ion channel modulation, will be critical for harnessing its therapeutic potential for sensory disorders and neurodegeneration. The role of neuritin 1 in synaptic plasticity and sensory nerve function: A potential therapeutic target for neuronal repair Running title: Neuritin 1 in synaptic plasticity Word Count: main body: 3285; including abstract, legends and references: 5704 Figure number: 2 Corresponding Authors: [email protected]; [email protected] The role of neuritin 1 in synaptic plasticity and sensory nerve function: A potential therapeutic target for neuronal repair Jyoti Agrawal 1,3 *, Mar Vives 1,3 *, Simon W Jones 2,4, Victoria Chapman 1,3*, Federico Dajas-Bailador 1,3* *Joint first authors

This work was supported by the Arthritis UK Pain Centre (grant number 20777), Arthritis Research UK (grant 23292) and by Medical Research Council (MR/W026961/1, MR/W026961/1). Affiliations 1. School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK 2. Department of Inflammation and Ageing, MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham B15 2TT, UK. 3. Arthritis UK Pain Centre, University of Nottingham, Nottingham NG7 2UH, UK. 4. National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, UK. *Corresponding Authors: [email protected]; [email protected]

Neuritin 1 (NRN1), initially identified as an activity-dependent gene in the rat brain, has emerged as a critical regulator of synaptic plasticity and neuronal development. This review synthesizes current understanding of NRN1’s involvement in the peripheral and central nervous systems, with a focus on neuronal repair after injury in particular in sensory neurones. We discuss the evidence that NRN1 interacts with brain derived neurotrophic factor (BDNF), nerve growth factor (NGF) and modulates injury-induced plasticity, influencing local axonal mRNA translation, potassium channel function, and calcium signalling. The activity-dependent modulation of AMPA receptors and ion channel trafficking by NRN1 supports a regulatory role in synaptic efficacy and neuronal excitability. NRN1 has been shown to contribute to structural and functional recovery in neurodegenerative conditions, including Alzheimer’s disease and post-ischemic injury. The regulation of NRN1 expression and trafficking is particularly relevant in models of nerve injury and diabetic peripheral neuropathy, where its expression is reduced in pathological states, but promotes axonal regeneration and Schwann cell survival when restored. NRN1 also influences non-neuronal cell signalling pathways, including VEGF and CXCR4 expression, which are associated with inflammation and persistent pain mechanisms. The diverse effects of NRN1 suggest it serves as a molecular integrator of neurotrophic, metabolic, and injury signals, making it a promising target for therapeutic strategies aimed at enhancing neuronal repair and potentially mitigating sensory nerve dysfunction. Understanding the molecular pathways regulated by NRN1, including local translation and ion channel modulation, will be critical for harnessing its therapeutic potential for sensory disorders and neurodegeneration.

Neuritin 1, Plasticity, Sensory Nerve, Nerve Repair Abbreviations AD Alzheimer’s disease Akt Protein Kinase B AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Arc activity regulated cytoskeleton-associated protein Bcl-2 B-cell lymphoma 2 BDNF brain-derived neurotrophic factor Ca 2+ calcium cAMP cyclic adenosine monophosphate CaN calcineurin Cav3.3 low-voltage-activated Ca v 3 channels CGN cerebellar granule neurones CGP15 candidate plasticity gene15 CREB cyclic AMP responsive element binding protein CXCL12 C-X-C motif chemokine ligand 12 CXCR4 C-X-C chemokine receptor type 4 DNA deoxyribonucleic acid DRG dorsal root ganglia ERK extracellular signal-regulated kinase EP ecliptic pHluorin GAP-43 growth associated protein 43 GDNF glial cell line-derived neurotrophic factor GFP green fluorescent protein GPI glycosylphosphatidyl inositol I A transient outward potassium current IGF1 insulin-like growth factor 1 IR insulin receptor Kv4.2 potassium voltage-gated channel subfamily D member 2 MCAO middle cerebral artery occlusion MEK mitogen-activated protein kinase kinase MiR-199a microRNA 199a mRNA messenger ribonucleic acid MTOR mammalian target of rapamycin NEURL1 neutralized-like 1 NF-200 neurofilament 200 NFATc4 nuclear factor of activated T-cells 4 Nfatc4-/- knockout of nuclear factor of activated T-cells 4 NGF nerve growth factor NMDA N-methyl-D-aspartate NRN1 neuritin1 NT-3 neurotrophin3 OA osteoarthritis PARP1 poly [ADP-ribose] polymerase 1 PI3K phosphoinositide 3-kinase PKA protein kinase A PSD95 postsynaptic density protein 95 p-Stat3 phosphorylated signal transducer and activator of transcription-3 p-Akt phosphorylated protein kinase B RGC retinal ganglion cell siRNA small interfering RNA STAT3 signal transducer and activator of transcription 3 SYN-38 synaptophysin TrkB tropomyosin receptor kinase B UTR untranslated region VEGF vascular endothelial growth factor WD Wallerian degeneration WT wild type

Neurotrophic factors play essential roles in the development, growth, survival and activity of the peripheral and central nervous system (Li et al., 2020), including the axonal regeneration of sensory neurons (Richner et al., 2014). The neurotrophic factor neuritin1 (NRN1), also known as candidate plasticity gene15 (CPG15), was first identified in a screen of plasticity related genes in the rat brain (Nedivi et al. 1993). NRN1 is encoded by Nrn1 and is a glycosylphosphatidyl inositol (GPI)-anchored protein which promotes activity dependent dendritic growth (Naeve et al., 1997, Cappelletti et al., 2007, Nedivi et al., 2001, Di Giovanni et al., 2005, Nedivi et al., 1998), with early findings indicating that it could also act as a soluble ligand (Naeve et al., 1997). Following these early findings, more recent developments in the field have prompted an appraisal of the role of NRN1 in neuronal circuitry plasticity. This is particularly timely given its emergence of a potential role in sensory nerve function and pain mechanisms. Here, we review the literature supporting a role for NRN1 in supporting peripheral and central nervous system function, with particular emphasis on its involvement in the stabilisation and modulation of excitatory synaptic structures, processes that are fundamental to neural plasticity, learning, and memory. We discuss the functional implications of NRN1 in the support of synaptic function in other types of plasticity, such as that occurring during the development of central sensitization in the spinal cord, and the interplay between NRN1 and other more widely studied neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) (Almodóvar-Payá et al., 2024, Cappelletti et al., 2007). We also examine the role of NRN1 in regulating sensory neuronal excitability through modulation of potassium currents and its influence on axonal integrity and repair in models of diabetic peripheral neuropathy, underscoring its potential as a therapeutic target for restoring sensory nerve function and alleviating pain signalling. 1.2 The role of NRN1 in neurodevelopment Since the first identification of NRN1 (Nedivi et al. 1993), its role in mediating neuronal plasticity, an essential mechanism supporting the development, maturation and refinement of the nervous system, has been consolidated (Zhou and Zhou, 2014). As summarised in previous work (Leslie and Nedivi, 2011), NRN1 regulates the structure and development of the cat visual system, consistent with a role in the formation of activity dependent synaptic connections (Corriveau et al. 1999, Lee and Nedivi 2002, Picard et al 2014). NRN1 has an established role in the development and maturation of hippocampal neuron connectivity (Lee et al., 2021; Son et al., 2012). Moreover, NRN1 knockout reduced spine stabilization in the mouse visual cortex, delayed axon and spine arbor development, and synapse maturation essential for efficient learning in the hippocampus (Fujino, T. et al. 2011). In Xenopus optic tectal neurons, NRN1 (described here as CPG15) expression led to the recruitment of functional AMPA receptors to synapses, promoting retinotectal synapse maturation (Cantallops et al., 2000). The expression of a truncated form of NRN1, lacking the GPI domain, eliminated the ability to promote axo-dendritic growth and synaptic maturation (Nedivi et al., 1998, Cantallops et al., 2000). While these results suggest that the GPI anchor is essential for the membrane-bound form of NRN1 to regulate neurodevelopment, in early development NRN1/CPG15 also has functional effects in the soluble form, acting as a survival factor for cortical progenitor cells (Putz et al., 2005). Indeed, endogenous CPG15 rescued cultured cortical neurons from apoptosis by preventing the activation of caspase 3, indicating a protective role of NRN1 during development (Putz et al., 2005). 1.3 The role of NRN1 in synaptic plasticity, pathology and repair NRN1 is highly expressed in the subicular regions of the hippocampus, being mainly concentrated in neuronal cell bodies, where it promotes neuritogenesis by stimulating neurite growth, an effect regulated by BDNF via TrkB signalling and neurotrophin 3 (Naeve et al. 1997). These effects of NRN1 on neurite growth were shown to be mediated by NRN1 acting as an upstream and negative regulator of neutralized-like 1 (NEURL1), which inhibits Notch signalling to promote neurite growth (Zhang et al., 2017). Upregulation of Notch inhibited axon extension and retraction of neurites (Zhang et al., 2017). The stimulatory effects of NRN1 on neurite growth were blocked by NEURL1, indicating the interplay between these molecules in regulating neuronal development and regeneration (Zhang et al. 2017). More recently, NRN1 was shown to inhibit Neurl1 activity by reducing ubiquitination and endocytosis of the target protein Jagged1 (ligand for notch1) (Zhu et al. 2023). In addition to these pathways, NRN1 overexpression promoted retinal ganglion cell survival and axonal regeneration via activated p-Stat3 and p-Akt1 signalling transduction pathways (Huang et al. 2021). Beyond its established role in neuronal development, mounting evidence supports a role for NRN1 in the adult brain during pathological conditions, where its re-expression may reflect an attempt to recapitulate developmental growth and repair pathways. For example, middle cerebral artery occlusion (MCAO) in rats has been associated with increased expression of NRN1, BDNF, and Arc mRNA in the peri-infarct cortex and dentate gyrus, regions implicated in post-stroke plasticity and functional recovery (Rickhag et al., 2007). Similarly, in a transient global ischemia model, both mRNA and protein levels of NRN1 were upregulated in the cortex and hippocampus, suggesting a broader involvement of NRN1 in injury-induced neuronal responses (Gao et al., 2014). These findings suggest that NRN1 can be reactivated in the mature brain under conditions of injury or stress, potentially contributing to synaptic remodelling, circuit reorganisation, or neuroprotective mechanisms reminiscent of its developmental functions. Indeed, NRN1 overexpression was associated with enhanced hippocampal protein expression of reparative molecules GAP-43 and SYN-38 and NF-200, which promoted neuroregenerative capacity and improved recovery of spatial learning and memory in a model of acute ischemia-reperfusion-induced brain injury in mice (Wan et al. 2020). In addition, hippocampal overexpression of NRN1 significantly reduced degradation of the DNA repair factor poly [ADP-ribose] polymerase 1 (PARP1) in the hippocampus (Wan et al. 2020). Consistent with a neuroadaptive role, NRN1 has also been implicated in maintaining functional connectivity in the human brain. Cortical and hippocampal NRN1 expression was significantly downregulated in the brains of Alzheimer’s disease (AD) patients, compared to age-matched controls (Choi et al., 2014). These changes were considered functionally relevant, as treatment with NRN1 restored dendritic spine density and synapse maturation in primary hippocampal neuron cultures derived from a transgenic mouse model of AD, returning them to levels observed in wild-type neurons (Choi et al., 2014). Moreover, lentiviral-mediated expression of NRN1 ameliorated the learning and memory impairments in the Tg2576 mice, which was suggested to result from improved spine density and synapse maturation (Choi et al. 2014). In line with these findings, hippocampal neuron cultures from Tg2576 mice exhibited decreased levels of NRN1 mRNA and reduced dendritic complexity compared to WT controls, which was reversed by exogenous application of NRN1 peptide (An et al., 2014). Related studies have shown that hippocampal miR-199a expression is increased in a mouse model of AD, and that miR-199a downregulates NRN1 expression by directly targeting the Nrn1 3’-UTR (Song et al., 2020). Mechanistic studies report that NRN1 can block amyloid beta 42-induced dendritic spine degeneration and hyperexcitability in primary rat hippocampal neuron cultures (Hurst et al., 2023). Extending beyond synaptic maintenance in complex brain regions such as the hippocampus, NRN1 also plays a role in the response to injury in long-projecting axons. For example, NRN1 expression in the retina was upregulated following optic nerve injury in mice (Azuchi et al., 2018). NRN1 knockout resulted in more severe retinal ganglion cell (RGC) loss and reduced activation of Akt and ERK, important mediators of pro-survival signalling in RGCs, suggesting a neuroprotective role of NRN1 in the retina (Azuchi et al., 2018). To observe the distribution of NRN1 in axons, Cantallops and Cline (2008) created a fusion protein of NRN1 with a highly pH-sensitive form of green fluorescent protein, eclipticpHluorin (EP). Expression of the EP-CPG15 protein in optical tectal explants and retinal ganglion cells from Xenopus tadpoles allowed assessment of CPG15 trafficking in vivo (Cantallops and Cline, 2008). CPG15 (NRN1) was delivered to the axon surface in a depolarisation- and calcium-dependent manner, indicating that the trafficking of CPG15 in neurones is an activity-dependent mechanism (Cantallops and Cline, 2008). Overall, these results suggest that NRN1 is translocated from cell bodies to sensory axons following activity or nerve injury, which is hypothesised to promote axon growth and potentially peripheral nerve regeneration. 1.4 Axonal transport of Nrn1 mRNA and local protein synthesis during nerve injury The concept of axonally localized mRNA translation has gained growing attention in recent years, particularly in the peripheral nervous system, where long distances between the cell body and axon terminals pose unique challenges for neuronal maintenance and plasticity. This mechanism allows for spatially restricted protein synthesis, enabling axons to rapidly adapt to environmental cues without requiring input from the soma. In sensory neurons, local translation is increasingly implicated in injury responses, regenerative growth, and peripheral sensitisation and pain modulation (Khoutorsky and Price, 2018, Gale et al., 2022). Driving the expression of NRN1-GFP constructs in dorsal root ganglia (DRG) neurones increased axon growth, while depletion of Nrn1 mRNA significantly reduced growth, supporting a role of NRN1 in sensory nerve development and function (Merianda et al., 2013). Local axonal synthesis of NRN1 may allow for rapid modulation of membrane excitability, cytoskeletal dynamics, or retrograde signalling—mechanisms that can influence both the thresholds and excitability of peripheral and central nerve terminals. Sciatic nerve injury has been shown to promote an increase in NRN1 mRNA and protein in the sciatic nerve axons, with a concurrent decrease in DRG cell bodies, (Merianda et al., 2013). This shift in NRN1 localisation from the DRG neuronal cell bodies to the axons during injury was driven by the 5’UTR of Nrn1, indicating a critical role for mRNA transport and local axonal synthesis in this process (Merianda et al., 2013). This redistribution suggests that local NRN1 production may be essential for supporting axonal regeneration and heightened sensitivity in damaged sensory neurons. Given the emerging importance of local protein synthesis in pain processing and sensitization, understanding the trafficking and translation of Nrn1 mRNA represents an important frontier in the study of neuronal plasticity and persistent pain. A recent study by Liu et al. (2024) demonstrated that NRN1 promotes Schwann cell dedifferentiation during Wallerian degeneration (WD) following peripheral nerve injury, identifying it as a key regulator of nerve regeneration. In this model, NRN1 activated the PI3K/Akt/mTOR signalling pathway, promoted demyelination of injured axons and facilitated the onset of WD. In addition, NRN1 enhanced the expression of neurotrophic factors such as NGF, GDNF, and BDNF, as well as the phagocytic and secretory activity of Schwann cells, collectively accelerating the subsequent regenerative process. These findings position NRN1 as an important modulator of the cellular reprogramming and trophic responses underpinning nerve repair, mechanisms that may extend to regenerative and plasticity processes in other neural systems. 1.5 Mechanisms of NRN1-Mediated Regulation of Ion Channel Function Initial studies in cortical primary neurones identifying NRN1 as an immediate early gene induced by Ca 2+ influx demonstrated a requirement for NMDA receptors and L type Ca 2+ channels (Fujino et al., 2003). The NRN1 promoter has multiple activity responsive transcription factor binding sites and members of the CREB family are both positive and negative regulators of NRN1 transcription (Fujino et al., 2003). In this study, NRN1 was induced by cAMP, however, PKA activation was not sufficient for induction and required concurrent synaptic stimulation by NMDA receptors and L-type Ca 2+ channels. More recently, NRN1 was shown to increase the frequency of miniature excitatory postsynaptic currents and glutamate release in a mouse medial prefrontal cortical preparation, an effect blocked by T-type Ca2+ channel inhibition (Lu et al. 2017). NRN1-driven increases in the surface expression of Cav3.3 were blocked by inhibition of insulin receptors or MEK/ERK activity (Lu et al., 2017). Proteomic analysis suggests a potential interaction between NRN1 and AMPA receptors (Schwenk et al., 2012, 2014), with functional studies demonstrating a direct interaction between them (Subramanian et al., 2019). In this study, NRN1 was required and sufficient for the activity-dependent recruitment of PSD95 to newly formed dendritic spines, and cell-autonomous NRN1 was shown to directly facilitate PSD95 recruitment and spine stabilization (Subramanian et al. 2019). 1.6 Effects of NRN1 at insulin receptors and roles in diabetic peripheral neuropathy NRN1 has been implicated in signalling pathways relevant to neuronal excitability and diabetes. NRN1 activates the insulin receptor (IR) and increases the density of transient outward potassium currents (I A ) via an up-regulation of the voltage gated K + channel Kv4.2 in cerebellar granule neurones (Yao et al. 2012). In this study NRN1-mediated activation of IR and mTOR/ERK (mammalian target of rapamycin/extracellular signal-regulated kinase) signalling pathways increased mRNA and protein expression of Kv4.2. More recent work demonstrated a requirement of Ca2 + /calcineurin (CaN)/nuclear factor of activated T-cells (NFATc4) in the NRN1 / IR pathway in CGN and HeLA cells (Yao et al., 2016). NFATc4 was recruited to the Kv4.2 gene promoter and the effects of NRN1 overexpression on neuronal excitability and dendritic spine formation were abrogated in Nfatc4-/- mice (Yao et al. 2016). Diabetic peripheral neuropathy is often characterised by pain in the extremities, foot ulcerations, amputation, leading to a reduced quality of life due to peripheral nervous system dysfunction (Elafros et al., 2022). mRNA expression levels of both NRN1 and NGF were significantly reduced in the sciatic nerve from diabetic rats (Ma et al. 2018), and this deficiency was suggested to contribute to the pathogenesis of diabetic neuropathy. Reduced axonal transport and expression of NRN1 was linked to NGF function in a model of diabetes in rats (Karamoysoyli et al. 2008). In vitro, NGF treatment increased the transcription and translation of NRN1 in sensory neurons and siRNA knockdown of NRN1 abolished NGF-mediated neurite outgrowth (Karamoysoyli et al. 2008). NRN1 is expressed as both a membrane form and a dominant soluble form in Schwann cells, and high glucose concentrations downregulate NRN1 levels, an effect associated with Schwann cell apoptosis (Min et al., 2012, Yan et al. 2018). The role of NRN1 in Schwann cell survival and function has been investigated in experimental models. NRN1 mRNA and protein levels were reduced in Schwann cells from an experimental model of diabetes and exogenous application of NRN1 increased cell viability and decreased apoptosis of Schwann cells by enhancing the Bcl-2 level and reducing caspase-3 activity (Xi et al. 2020). Interestingly, co-culture of diabetic DRG neurons with Schwann cells pre-treated with exogenous NRN1 ameliorated reductions in DRG neurite outgrowth and NGF levels (Xi et al., 2020). Administration of insulin growth factor (IGF-1), which attenuates high glucose induced apoptosis of Schwann cells, was also associated with a reduction in NRN1 levels (Yan et al., 2018). IGF-1 is implicated in modulating the responses of the sensory nociceptive neurones via the activation of IGF-1R and the enhancement of T-type channel currents to increase the excitability of DRG neurons, which can increase responses to nociceptive stimuli (Zhang et al. 2014). However, the potential contribution of NRN1 to this effect in sensory neurones remains to be determined. Collectively, these findings highlight NRN1 as an integrator of metabolic and neurotrophic signalling in both neurons and Schwann cells, with emerging relevance to the pathogenesis of diabetic peripheral neuropathy. 1.7 Roles of NRN1 in non-nervous system cells Roles for NRN1 in other non-neuronal cells have also been identified, particularly inflammatory signalling mechanisms relevant to sensory nerve sensitization. The nrn1 gene is co-expressed with CXCR4 in renal cell carcinoma cells, and NRN1 overexpression significantly upregulated CXCR4 mRNA levels, although the mechanism underlying this effect is unclear (Kamada et al., 2021). As discussed above NRN1 binding to the insulin receptor activates NFATc4, which is proposed to bind to the CXCR4 promoter to increase CXCR4 expression (Yao et al., 2016; Cole et al., 2020). CXCR4 and its ligand CXCL12 play an important role in the mechanisms underpinning neuropathic pain mechanisms and contribute to central sensitisation by promoting inflammatory signalling in the spinal dorsal horn following injury (Liu et al., 2019; Yu et al., 2017). The ability of NRN1 to regulate the transcriptional control of CXCR4 may be relevant for the regulation of pain signalling and warrants further investigation. Overexpression of NRN1 in pulmonary endothelial cells increased VEGFR mRNA and protein levels (Zhang et al., 2019) and inhibited the expression of Notch-associated factors, (Yang et al., 2021). NRN1 has been shown to regulate melanoma signalling, linking Notch and STAT3 signalling leading to an upregulation of targets such as Vegf A (Devitt et al., 2024). The NRN1-dependent transcriptional regulation of VEGF has implications for angiogenesis and inflammation and sensory neuron sensitisation and pain (Llorián-Salvador & González-Rodríguez, 2018, Zhang et al., 2019). These interactions are supported by the finding that NRN1 mRNA expression is increased in the synovium at the site of patient-reported pain in people with early stage osteoarthritis (OA) (Nanus et al. 2021). Mechanistic studies demonstrated that the secretome from synovial fibroblasts (fibroblast-like synoviocytes) isolated from this pain-associated synovial tissue promoted neurite outgrowth and neuronal survival of rat primary DRG neurone cultures (Nanus et al., 2021). These findings provide novel insights into the potential peripheral sources of NRN1 during OA and inflammation, suggesting that beyond being a local cue for neurite growth, NRN1 may signal between cell types to promote sensitisation of sensory nerves.

NRN1 plays a fundamental role in the stabilisation and maturation of excitatory synapses and in promoting synaptic plasticity. As a membrane-bound ligand highly expressed during key developmental periods, NRN1 coordinates the growth of opposing dendritic and axonal arbors and facilitates the maturation of their synaptic connections. Its ability to drive neuroplasticity has been demonstrated in hippocampal-dependent learning tasks and object recognition, and its influence on synaptic refinement positions NRN1 as a key player in experience-dependent plasticity, including in the mammalian visual system. Beyond development, evidence supports an ongoing role for NRN1 in activity-dependent synaptic modulation, injury-induced plasticity, and neuronal repair. These functions are increasingly linked to pathological states, including neurodegeneration, diabetic neuropathy and persistent pain, where NRN1 reactivation or dysregulation may drive adaptive or maladaptive changes in neural circuits. Collectively, recent studies support NRN1 as a critical modulator of neuronal network connectivity, and that the underpinning signalling pathways may offer promising targets for therapeutic intervention in disorders of plasticity and sensory nerve dysfunction.

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Neuritin affects the activity of neuralized-like 1 by promoting degradation and weakening its affinity for substrate. Acta biochimica et biophysica Sinica, 55 (10), 1650–1658. https://doi.org/10.3724/abbs.2023098. Legends Figure 1: Role of Neuritin (NRN1) in Synaptic Plasticity and Sensory Nerve Function. NRN1 mediated synaptic plasticity is mediated by multiple ion channels, including NMDA receptors and voltage-gated calcium channels (Fujino et al., 2003). NRN1 promotes axonal growth and repair. NRN1 has complex effects on excitability via changes in both glutamate signalling and increased potassium currents (Lu et al. 2017, Yao et al. 2012). NRN1 can inhibit neuronal apoptosis by preventing activation of caspase-3 (Putz et al., 2005, Yao et al. 2012, 2016). (Created with Biorender.com) Figure 2 : Schematic representation of NRN1-mediated signalling pathways and their role in neuronal function. (a) NRN1 (Neuritin 1) when bound to Insulin receptor (IR) activates multiple intracellular pathways, including the NFAT, MAPK, and PI3K/AKT/mTOR cascades via calcium influx and receptor-mediated signalling, which enhances synaptic plasticity and neuronal regeneration. (b)NRN1 in membrane bound form inhibits Caspase-3 activity, thereby reducing neuronal apoptosis. NRN1 also regulates Notch signalling through NEURL1, which suppresses the formation of the Notch intracellular domain (NICD), influencing neuronal differentiation (Yao et al. 2016, Zhang et al. 2017, Gao et al., 2014). Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Collection

Authors Metrics & Citations Metrics Article Usage 462views 169downloads Citations Download citation Jyoti Agrawal, Mar Escola, Simon Jones, et al. The role of neuritin 1 in synaptic plasticity and sensory nerve function: A potential therapeutic target for neuronal repair. Authorea. 13 November 2025. DOI: https://doi.org/10.22541/au.176302880.07195229/v1 DOI: https://doi.org/10.22541/au.176302880.07195229/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.