{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:27:59Z","timestamp":1785403679332,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,2]]},"group-title":"Neuroscience","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R35GM146782"],"award-info":[{"award-number":["R35GM146782"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R56MH096881"],"award-info":[{"award-number":["R56MH096881"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01cmst727","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Autism Spectrum Program of Excelence"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Heterozygous deletions in\n                  <jats:italic>NRXN1<\/jats:italic>\n                  , encoding the presynaptic adhesion molecule Neurexin 1, are among the most frequently identified rare variants in schizophrenia and other neuropsychiatric disorders. Patient sequencing has revealed that 3\u2019 deletions within\n                  <jats:italic>NRXN1<\/jats:italic>\n                  generate novel isoforms not produced from the intact locus, yet whether these isoforms are functional, passively non-functional, or actively pathogenic\n                  <jats:italic>in vivo<\/jats:italic>\n                  is still not clear. To address this, we expressed eight human\n                  <jats:italic>NRXN1<\/jats:italic>\n                  isoforms in\n                  <jats:italic>C. elegans<\/jats:italic>\n                  neurons including four control isoforms and four 3\u2019 deletion variant isoforms identified in schizophrenia patient cell lines, and characterized their effects on protein localization and two independent behaviors: a food deprivation response and social feeding behaviors. Most human isoforms showed expression and localization within the nerve ring and neurons similar to the\n                  <jats:italic>C. elegans<\/jats:italic>\n                  ortholog, NRX-1; however, several isoforms, particularly among the 3\u2019 deletion variants, displayed aberrant accumulation in neuronal cell bodies or as puncta in neuropil. Functionally, isoforms fell into one of three categories: no effect on\n                  <jats:italic>nrx-1<\/jats:italic>\n                  loss-of-function behavioral phenotypes, partial rescue, or gain of function, with multiple isoforms showing differences between the behaviors. Strikingly, two 3\u2019 deletion isoforms produced gain-of-function behavioral phenotypes more severe than the\n                  <jats:italic>nrx-1<\/jats:italic>\n                  null mutant, demonstrating that these patient-derived variants can be actively pathogenic. These results establish\n                  <jats:italic>C. elegans<\/jats:italic>\n                  as a tractable\n                  <jats:italic>in vivo<\/jats:italic>\n                  platform for dissecting the isoform-specific functional consequences of\n                  <jats:italic>NRXN1<\/jats:italic>\n                  variants and suggest that strategies for\n                  <jats:italic>NRXN1<\/jats:italic>\n                  -associated neuropsychiatric diseases must account for both loss-of-function and gain-of-function isoform mechanisms.\n                <\/jats:p>","DOI":"10.1101\/2025.08.29.672776","type":"posted-content","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T16:55:12Z","timestamp":1756832112000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>In vivo<\/i>\n                  dissection of human\n                  <i>NRXN1<\/i>\n                  isoforms reveals gain-of-function pathogenicity of schizophrenia-associated 3\u2019 deletions"],"prefix":"10.64898","author":[{"given":"Dustin","family":"Haskell","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":[{"key":"2026032108550643000_2025.08.29.672776v3.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.10.037"},{"key":"2026032108550643000_2025.08.29.672776v3.2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31327"},{"key":"2026032108550643000_2025.08.29.672776v3.3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008922"},{"key":"2026032108550643000_2025.08.29.672776v3.4","first-page":"742","article-title":"Understanding the Emergence of Neuropsychiatric Disorders With Network Neuroscience","volume":"3","year":"2018","journal-title":"Biol. 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