{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:42:38Z","timestamp":1788846158483,"version":"build-2803163510"},"posted":{"date-parts":[[2026,2,7]]},"group-title":"Neuroscience","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T00:00:00Z","timestamp":1770422400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Autism Spectrum Program of Excellence"},{"award":["1R35GM146782"],"award-info":[{"award-number":["1R35GM146782"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Neurexins are synaptic adhesion molecules associated with neurologic changes in humans, including neurodevelopmental delay, autism, schizophrenia, Tourette syndrome, and seizures. The\n                  <jats:italic>NRXN1<\/jats:italic>\n                  gene produces &gt;100 protein isoforms through alternative promoters and extensive splicing, which are differentially impacted by\n                  <jats:italic>NRXN1<\/jats:italic>\n                  variants found in patients. Yet pharmacologic targeting of\n                  <jats:italic>NRXN1<\/jats:italic>\n                  isoforms or deletions has not been comprehensively studied. Here, we developed a behavioral screening approach in\n                  <jats:italic>C. elegans<\/jats:italic>\n                  to identify small molecule compounds that modify the decreased activity levels caused by isoform-specific deletions of neurexin(\n                  <jats:italic>nrx-1<\/jats:italic>\n                  ). Screening 190 compounds, we discovered that monoamine-targeting compounds differentially improve behavioral phenotypes depending on which\n                  <jats:italic>nrx-1<\/jats:italic>\n                  isoforms are disrupted. Broad modulation of monoamine signaling, or antagonism of specific serotonin receptors, are required to increase the activity of both alleles tested. The FDA-approved atypical antipsychotic olanzapine was the sole validated compound achieving Z-scores &gt;2 in both screens, which notably also rescued behavioral phenotypes of\n                  <jats:italic>C. elegans<\/jats:italic>\n                  harboring a conserved autism-associated\n                  <jats:italic>NRXN1<\/jats:italic>\n                  missense variant (L18Q\/L16Q) identified in human patients. In\n                  <jats:italic>Drosophila Nrx-1<\/jats:italic>\n                  mutants, olanzapine uniquely and significantly improved activity deficits and extended survival, demonstrating evolutionary conservation of our findings. Multi-behavior testing revealed pharmacological specificity: olanzapine improved both activity and social feeding phenotypes of\n                  <jats:italic>nrx-1<\/jats:italic>\n                  alleles, while asenapine maleate improved activity, but worsened social feeding, indicating distinct impacts across behavioral domains. Our findings establish monoamine modulation as a conserved compensatory mechanism for neurexin loss, identify olanzapine as a lead compound for targeting neurexin loss, and demonstrate that allele stratification and pharmacogenomic approaches are needed for precision intervention in behavioral conditions.\n                <\/jats:p>\n                <jats:p>\n                  Neurexins are synaptic adhesion molecules implicated in autism, schizophrenia, and neurodevelopmental disorders.\n                  <jats:italic>NRXN1<\/jats:italic>\n                  produces over 100 isoforms differentially affected by patient variants, yet pharmacologic targeting has not been systematically studied. We developed a\n                  <jats:italic>C. elegans<\/jats:italic>\n                  behavioral screen to identify compounds rescuing activity deficits caused by isoform-specific deletions. Screening 190 compounds, we discovered that monoamine-targeting drugs differentially improved behavioral phenotypes depending on which isoforms were disrupted. The FDA-approved antipsychotic olanzapine uniquely achieved robust rescue (Z-scores &gt;2) across all genetic backgrounds tested, including a conserved autism-associated\n                  <jats:italic>NRXN1<\/jats:italic>\n                  missense variant (L18Q\/L16Q) identified in patients. Olanzapine\u2019s efficacy was conserved in\n                  <jats:italic>Drosophila Nrx-1<\/jats:italic>\n                  mutants, improving activity and extending survival. Multi-behavior testing revealed pharmacological specificity: olanzapine rescued both activity and social feeding phenotypes, while asenapine differentially affected behavioral domains. Our findings establish monoamine modulation as a compensatory mechanism for neurexin loss and identify olanzapine as a therapeutic lead for precision intervention in neurexin-associated disorders.\n                <\/jats:p>","DOI":"10.64898\/2026.02.06.703315","type":"posted-content","created":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T01:00:18Z","timestamp":1770512418000},"source":"Crossref","is-referenced-by-count":2,"title":["Allele-specific rescue of neurexin behavioral phenotypes by monoamine-targeting compounds"],"prefix":"10.64898","author":[{"given":"William R.","family":"Smisko","sequence":"first","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"},{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0656-2234","authenticated-orcid":false,"given":"William R.","family":"Haury","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"},{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7593-8376","authenticated-orcid":false,"given":"Michele","family":"Perni","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"},{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8628-1506","authenticated-orcid":false,"given":"Rebecca","family":"Kalik","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"},{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0267-4256","authenticated-orcid":false,"given":"Jhelaine","family":"Palo","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6029-5846","authenticated-orcid":false,"given":"Brandon L.","family":"Bastien","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9893-1334","authenticated-orcid":false,"given":"Jadwiga N.","family":"Bilchak","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raheem","family":"Khadour","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0190-7339","authenticated-orcid":false,"given":"Thomas A.","family":"Jongens","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"},{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine, Philadelphia, PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Kayser","sequence":"additional","affiliation":[{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine, Philadelphia, PA USA"},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA"}],"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, Philadelphia, PA USA"},{"name":"Autism Spectrum Program of Excellence, Perelman School of Medicine, Philadelphia, PA 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