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Roles of NRXN1 in neuropsychiatric disorders: from genetic lesion to molecular mechanism

Liu, Jiaxiang, Zhang, Yanxuan, Jin, Ruijia, Zhu, Yuxin, Chen, Jianrui·2026·Frontiers in Neuroscience
DOI 10.3389/fnins.2026.1808921PMC PMC13212319
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Abstract

Numerous neuropsychiatric disorders frequently exhibit overlapping genetic risk factors, implying the molecular basis for their comorbidity. Nevertheless, the pathogenesis of these disorders remains elusive, particularly regarding how genetic variations impair the physiological function of risk genes and contribute to disease phenotypes. Neurexin 1 protein, encoded by NRXN1 gene, belongs to the neurexin family of presynaptic adhesion molecules. And neurexin 1 is involved in synaptogenesis and the maintenance of synaptic action. Genetic variations of NRXN1 have been demonstrated to be associated with a spectrum of neuropsychiatric disorders. Herein, this review focuses on the most recent and relevant literature concerning the genetic and molecular mechanisms through which NRXN1 variants contribute to the pathogenesis of neuropsychiatric disorders, particularly schizophrenia and autism spectrum disorder. Among them, we propose the isoform-dependent excitation-inhibition imbalance hypothesis of NRXN1 in autism spectrum disorder. And this hypothesis may account for both the elevated and decreased excitation-inhibition ratios observed in diverse individuals with autism spectrum disorder. Moreover, both schizophrenia and autism spectrum disorder involve deletions and alternative splicing of NRXN1 , offering molecular evidence for their comorbidity. Then, we analyzed and summarized the current research status of NRXN1 in other neuropsychiatric disorders, including attention-deficit hyperactivity disorder, insomnia, epilepsy, suicide, and depression. Additionally, available limited researches on NRXN1 -targeted therapeutic strategies and associated pharmacological studies are also incorporated. Finally, we discussed existing challenges in NRXN1 research within the context of neuropsychiatric disorders and proposed potential avenues to overcome these obstacles.

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Figures

Figure 1 Genomic organization of NRXN1 gene and structures of its protein isoforms neurexin 1α and neurexin 1β. NRXN1 gene consists of 24 exons. Dotted lines indicate the correspondence between exons and protein domains. Neurexin 1α is transcribed from the promoter of α located upstream of exon 1, whereas neurexin 1β is transcribed from the promoter of β located downstream of exon 18. The neurexin 1α isoform contains three EGF domains, six LNS domains, a carboxy-terminal glycosylated region, a transmembrane domain, and a PDZ domain-binding motif. Neurexin 1β isoform contains an LNS domain, a carboxy-terminal glycosylated region, a transmembrane domain, and a PDZ domain-binding motif. The positions of SS1-6 are marked in the figure.
Figure 1 Genomic organization of NRXN1 gene and structures of its protein isoforms neurexin 1α and neurexin 1β. NRXN1 gene consists of 24 exons. Dotted lines indicate the correspondence between exons and protein domains. Neurexin 1α is transcribed from the promoter of α located upstream of exon 1, whereas neurexin 1β is transcribed from the promoter of β located downstream of exon 18. The neurexin 1α isoform contains three EGF domains, six LNS domains, a carboxy-terminal glycosylated region, a transmembrane domain, and a PDZ domain-binding motif. Neurexin 1β isoform contains an LNS domain, a carboxy-terminal glycosylated region, a transmembrane domain, and a PDZ domain-binding motif. The positions of SS1-6 are marked in the figure.CC BY · PubMed Central
Figure 2 Molecular interactions between main neurexin isoforms and corresponding ligands in terms of synapse development/function. The neurexin 1α and neurexin 1β interact with a series of synaptic ligands to propel the assembly of functional presynaptic and postsynaptic structures.
Figure 2 Molecular interactions between main neurexin isoforms and corresponding ligands in terms of synapse development/function. The neurexin 1α and neurexin 1β interact with a series of synaptic ligands to propel the assembly of functional presynaptic and postsynaptic structures.CC BY · PubMed Central
Figure 3 Impacts of mutated NRXN1 in schizophrenia, attention-deficit hyperactivity disorder, insomnia, epilepsy and suicide. In schizophrenia (A), 5′ deletions in the NRXN1 gene contribute to the formation of aberrant, allele-specific chromatin loops, leading to the downregulation of neurexin-1 protein. This downregulation can also be caused by sex-specific methylation of the NRXN1 locus, a process modulated by the miRNA MIR-137. The resulting deficit in neurexin 1 impairs its critical interactions with binding partners, such as neuroligin and/or DGCR2, thereby decreasing mEPSC frequency and dendritic spine/synapse density. Concomitantly, the decrease in neurexin-1 triggers a secondary upregulation of CASK. Moreover, the pathological cascade is potentiated by the presence of anti-neurexin 1α antibodies, which are specifically detected in schizophrenia patients and further disrupt the neurexin 1–neuroligin interaction. In attention-deficit hyperactivity disorder (B), neurexin 1 deficiency mediates the downregulation of postsynaptic molecules (SYN1, PSD95, and GAP43) via the MALAT1-miR-141–3p/200a-3p-Nrxn1 axis. In insomnia (C), reduced neurexin-1 levels are associated with shortened slow-wave sleep duration, ultimately contributing to circadian rhythm disruption. In epilepsy (D), the deficit impairs the specific interaction between neurexin 1 and PSD-95. In suicide (E), the binding affinity between neurexin-1 and LRRTM2 is enhanced.
Figure 3 Impacts of mutated NRXN1 in schizophrenia, attention-deficit hyperactivity disorder, insomnia, epilepsy and suicide. In schizophrenia (A), 5′ deletions in the NRXN1 gene contribute to the formation of aberrant, allele-specific chromatin loops, leading to the downregulation of neurexin-1 protein. This downregulation can also be caused by sex-specific methylation of the NRXN1 locus, a process modulated by the miRNA MIR-137. The resulting deficit in neurexin 1 impairs its critical interactions with binding partners, such as neuroligin and/or DGCR2, thereby decreasing mEPSC frequency and dendritic spine/synapse density. Concomitantly, the decrease in neurexin-1 triggers a secondary upregulation of CASK. Moreover, the pathological cascade is potentiated by the presence of anti-neurexin 1α antibodies, which are specifically detected in schizophrenia patients and further disrupt the neurexin 1–neuroligin interaction. In attention-deficit hyperactivity disorder (B), neurexin 1 deficiency mediates the downregulation of postsynaptic molecules (SYN1, PSD95, and GAP43) via the MALAT1-miR-141–3p/200a-3p-Nrxn1 axis. In insomnia (C), reduced neurexin-1 levels are associated with shortened slow-wave sleep duration, ultimately contributing to circadian rhythm disruption. In epilepsy (D), the deficit impairs the specific interaction between neurexin 1 and PSD-95. In suicide (E), the binding affinity between neurexin-1 and LRRTM2 is enhanced.CC BY · PubMed Central
Figure 4 Isoform-dependent E-I imbalance hypothesis of NRXN1 in autism spectrum disorder. In glutamatergic neurons, deficiency of neurexin 1β disrupts its interaction with neuroligin 1. This impairment consequently inhibits glutamate-mediated signal transduction, thereby reducing the activity of these excitatory neurons. In GABAergic neurons, deficiency of neurexin 1α disrupts its connection with neuroligin 2, resulting in reduced GABAergic signaling and activity of these inhibitory neurons. Diminished excitatory glutamatergic and inhibitory GABAergic activity both contribute to the E-I imbalance in the dorsolateral prefrontal cortex. This region contains excitatory glutamatergic neurons (including pyramidal neurons in layers 2–5) as well as diverse inhibitory GABAergic neurons: Lhx6 + neurons (PV+ and SST+ subclasses) and Prox1 + neurons (including VIP+ and Lamp5+ subclasses).
Figure 4 Isoform-dependent E-I imbalance hypothesis of NRXN1 in autism spectrum disorder. In glutamatergic neurons, deficiency of neurexin 1β disrupts its interaction with neuroligin 1. This impairment consequently inhibits glutamate-mediated signal transduction, thereby reducing the activity of these excitatory neurons. In GABAergic neurons, deficiency of neurexin 1α disrupts its connection with neuroligin 2, resulting in reduced GABAergic signaling and activity of these inhibitory neurons. Diminished excitatory glutamatergic and inhibitory GABAergic activity both contribute to the E-I imbalance in the dorsolateral prefrontal cortex. This region contains excitatory glutamatergic neurons (including pyramidal neurons in layers 2–5) as well as diverse inhibitory GABAergic neurons: Lhx6 + neurons (PV+ and SST+ subclasses) and Prox1 + neurons (including VIP+ and Lamp5+ subclasses).CC BY · PubMed Central

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Cited by

Metadata

Authors
Liu, J., Zhang, Y., Jin, R., Zhu, Y., & Chen, J.
Affiliations
  • Queen Mary School, Medical Department, Nanchang University
  • Hospital of Stomatology, Jilin University
  • Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2026-05-13
Volume
20
ISSN
1662-453X
DOI
10.3389/fnins.2026.1808921
PMC
PMC13212319
Cited by
1
References
14
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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