{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T16:41:25Z","timestamp":1793032885383,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,4]]},"group-title":"Neuroscience","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"award":["R35GM146782"],"award-info":[{"award-number":["R35GM146782"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Neurexins are critical synaptic cell adhesion molecules that play many roles in modulating neurotransmitter release and synaptic function, and are high-confidence risk genes for neurodevelopmental conditions such as autism. Understanding the function of the neurexin superfamily has been challenging in mammalian systems that have 3 genes (\n                  <jats:italic>NRXN1-3<\/jats:italic>\n                  ) that encode 2-3 major isoforms, which undergo extensive alternative splicing and generate thousands of transcripts. In contrast to mammals,\n                  <jats:italic>C. elegans<\/jats:italic>\n                  has a single gene,\n                  <jats:italic>nrx-1<\/jats:italic>\n                  , encoding only long \u03b1 and short \u03b3 isoforms. Neurexins canonically regulate synapse morphology and function in a neuron- and context-specific manner, through mechanisms related to release of chemical neurotransmitters and receptors. Whether neurexins (\n                  <jats:italic>nrx-1<\/jats:italic>\n                  ) impact other secretory molecules such as neuropeptides (NPs) and NP containing dense-core vesicles (DCVs) is not well understood. Here, we report that loss of\n                  <jats:italic>nrx-1<\/jats:italic>\n                  increases the release of multiple NPs from cholinergic motor neurons in\n                  <jats:italic>C. elegans<\/jats:italic>\n                  . Using tissue specific expression and degradation of endogenous NRX-1, we find that\n                  <jats:italic>nrx-1<\/jats:italic>\n                  functions in NP release from cholinergic neurons in a cell-autonomous manner. We confirm that loss of\n                  <jats:italic>nrx-1<\/jats:italic>\n                  impacts cholinergic active-zone number, but also find it regulates the clustering, distribution, and expression of the DCV protein, IDA-1 (PTPRN), and the DCV secretion regulator, UNC-31 (CADPS). We find that\n                  <jats:italic>nrx-1<\/jats:italic>\n                  functions to maintain separation and juxtaposition of neurotransmitter and NP release sites and DCV localization. Loss of cholinergic excitation (\n                  <jats:italic>unc-17<\/jats:italic>\n                  ) or GABAergic inhibition (\n                  <jats:italic>unc-25<\/jats:italic>\n                  ) did not impact cholinergic NP release, but that the increased NP release upon loss of\n                  <jats:italic>nrx-1<\/jats:italic>\n                  is dependent on the calcium channel\n                  <jats:italic>unc-2<\/jats:italic>\n                  . We find that neurexins can regulate NP signaling, a novel mechanism to modify circuits and behaviors, and of potential importance for\n                  <jats:italic>NRXN1<\/jats:italic>\n                  associated human conditions.\n                <\/jats:p>","DOI":"10.64898\/2026.08.31.748337","type":"posted-content","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T21:30:13Z","timestamp":1788557413000},"source":"Crossref","is-referenced-by-count":0,"title":["Neurexin mediates neuropeptide release from cholinergic motor neurons through dense-core vesicle localization"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8533-1885","authenticated-orcid":false,"given":"Vina","family":"Tikiyani","sequence":"first","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8865-3062","authenticated-orcid":false,"given":"Michael P.","family":"Hart","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania"},{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"3","key":"2026102609151156000_2026.08.31.748337v3.1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.ejmg.2018.07.015","article-title":"NRXN1 Deletion Syndrome; Phenotypic and Penetrance Data from 34 Families","volume":"62","year":"2019","journal-title":"European Journal of Medical Genetics"},{"issue":"1","key":"2026102609151156000_2026.08.31.748337v3.2","doi-asserted-by":"crossref","first-page":"448","DOI":"10.18295\/2075-0528.3002","article-title":"Clinical Phenotypes Associated with NRXN1 Deletions in Five Children with Autism Spectrum Disorder in Oman","volume":"26","year":"2026","journal-title":"Sultan Qaboos University Medical Journal"},{"issue":"1","key":"2026102609151156000_2026.08.31.748337v3.3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1742-2094-7-48","article-title":"Neurotensin Is Increased in Serum of Young Children with Autistic Disorder","volume":"7","year":"2010","journal-title":"Journal of Neuroinflammation"},{"key":"2026102609151156000_2026.08.31.748337v3.4","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyab006"},{"issue":"1","key":"2026102609151156000_2026.08.31.748337v3.5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.neuron.2011.05.034","article-title":"The Immunoglobulin Super Family Protein RIG-3 Prevents Synaptic Potentiation and Regulates Wnt Signaling","volume":"71","year":"2011","journal-title":"Neuron"},{"issue":"1","key":"2026102609151156000_2026.08.31.748337v3.6","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/s41398-023-02668-z","article-title":"Distinct Neurexin Isoforms Cooperate to Initiate and Maintain Foraging Activity","volume":"13","year":"2023","journal-title":"Translational Psychiatry"},{"key":"2026102609151156000_2026.08.31.748337v3.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81609-8"},{"key":"2026102609151156000_2026.08.31.748337v3.8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/B978-0-12-819973-2.00009-5","article-title":"The Promiscuity of the Oxytocin-Vasopressin Systems and Their Involvement in Autism Spectrum Disorder","volume":"182","year":"2021","journal-title":"Handbook of Clinical Neurology, Handbook of clinical neurology"},{"key":"2026102609151156000_2026.08.31.748337v3.9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.318659"},{"key":"2026102609151156000_2026.08.31.748337v3.10","doi-asserted-by":"publisher","DOI":"10.1051\/medsci\/20031967725"},{"key":"2026102609151156000_2026.08.31.748337v3.11","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.16161"},{"key":"2026102609151156000_2026.08.31.748337v3.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2016.09.005"},{"issue":"e85058","key":"2026102609151156000_2026.08.31.748337v3.13","first-page":"e85058","article-title":"Neurexins in Serotonergic Neurons Regulate Neuronal Survival, Serotonin Transmission, and Complex Mouse Behaviors","volume":"12","year":"2023","journal-title":"eLife"},{"issue":"1","key":"2026102609151156000_2026.08.31.748337v3.14","doi-asserted-by":"crossref","first-page":"9301","DOI":"10.1038\/s41467-024-53590-x","article-title":"Conserved Autism-Associated Genes Tune Social Feeding Behavior in C. 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