{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeurexin‐3 (NRXN3) is a member of the neurexin family of neuronal adhesion proteins that are essential for specifying and maintaining synaptic contacts. NRXN3 exists in multiple isoforms produced by alternative promoters and splicing events, which result in receptor‐like transmembrane proteins (both α‐ and β‐forms) capable of binding diverse extracellular ligands such as neuroligins and neurexophilins. Moreover, post‐translational modifications—including cleavage by secretases—generate soluble extracellular domains and intracellular fragments that can modulate presynaptic release probability and synaptic morphology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its classical synaptic functions, NRXN3 is increasingly implicated in neurodevelopmental and neuropsychiatric disorders. Rare deletions and point mutations affecting NRXN3 exons have been observed in individuals with autism spectrum disorder, suggesting that disruptions in synaptic adhesion and signaling contribute to developmental phenotypes. Alternative splicing at key donor sites further alters the balance between transmembrane and soluble NRXN3 isoforms, a change that has been associated with addiction phenotypes such as nicotine dependence and altered presynaptic neurotransmission in psychiatric conditions including schizophrenia and borderline personality features. Furthermore, NRXN3 variants have also been linked to environmental stress outcomes—for example, an association with delayed encephalopathy following carbon monoxide poisoning—and gene × environment studies support its role in modulating brain gene expression in addiction‐related behaviors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central roles in the brain, NRXN3 has also been associated with metabolic and peripheral functions. Genome‑wide association studies have linked common variants in NRXN3 with increased waist circumference, body mass index, and obesity risk—findings that support the concept of central nervous system regulation of energy balance and reward‐related feeding behavior. Intriguingly, differential expression and tissue‑specific splicing of NRXN3 (including expression in the heart) indicate roles in intercellular adhesion outside the brain, while regulatory mechanisms involving non‑coding circular RNAs can modulate NRXN3 activity in tumors such as glioma. Together, these observations highlight the multifaceted functions of NRXN3 in both neural circuits and peripheral tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andrea K Vaags, Anath C Lionel, Daisuke Sato, et al. 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