{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:04:05Z","timestamp":1790622245273,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Neuroscience","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01NS117585"],"award-info":[{"award-number":["R01NS117585"]}]},{"name":"National Institutes of Health","award":["R01NS123154"],"award-info":[{"award-number":["R01NS123154"]}]},{"name":"National Institutes of Health","award":["R56NS097726"],"award-info":[{"award-number":["R56NS097726"]}]},{"id":[{"id":"https:\/\/ror.org\/01nz0vz73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Genetic loss-of-function (LoF) variants in\n                  <jats:italic>SCN2A<\/jats:italic>\n                  , a gene encoding the voltage-gated sodium channel Nav1.2, have been identified as one of the foremost monogenic causes of autism spectrum disorder (ASD). ASD encompasses a broad spectrum of behavioral phenotypes, with impaired sociability as a core characteristic. We have established\n                  <jats:italic>Scn2a<\/jats:italic>\n                  -deficient mice (\n                  <jats:italic>\n                    Scn2a\n                    <jats:sup>gt\/gt<\/jats:sup>\n                  <\/jats:italic>\n                  ) to model\n                  <jats:italic>Scn2a<\/jats:italic>\n                  -related ASD and found that this model recapitulates social impairment, exhibiting severe social deficits.\n                  <jats:italic>\n                    Scn2a\n                    <jats:sup>gt\/gt<\/jats:sup>\n                  <\/jats:italic>\n                  mice exhibit neuronal hyperexcitability and a marked global reduction in potassium channel expression, which plays a crucial role in maintaining the resting membrane potential and repolarizing neurons after an action potential. Among these downregulated potassium channels, potassium voltage-gated channel subfamily A member 1 (Kv1.1) was one of the most affected. To explore whether Kv1.1 could be a potential therapeutic target in\n                  <jats:italic>SCN2A<\/jats:italic>\n                  -related ASD, we evaluated the\n                  <jats:italic>in vivo<\/jats:italic>\n                  efficacy of a genetic construct driven by the CaMKII\u03b1 promoter that allows for exogenous expression of human Kv1.1 (hKv1.1) in principal neurons. In\n                  <jats:italic>\n                    Scn2a\n                    <jats:sup>gt\/gt<\/jats:sup>\n                  <\/jats:italic>\n                  mice, we found that hKv1.1 expression normalizes neuronal hyperexcitability. Importantly, doxycycline-induced hKv1.1 expression enhances sociability in\n                  <jats:italic>Scn2a<\/jats:italic>\n                  -deficient mice without influencing social behavior in wild-type mice, and this effect was reversed upon doxycycline withdrawal. Overall, we demonstrate the successful use of an inducible AAV-mediated gene delivery system to supplement hKv1.1 expression to mitigate neuronal hyperexcitability and ameliorate social impairments in a mouse model of\n                  <jats:italic>SCN2A<\/jats:italic>\n                  -related ASD. These findings highlight the contribution of Kv1.1 to\n                  <jats:italic>SCN2A<\/jats:italic>\n                  -associated pathophysiology and its potential as a therapeutic target for severe social deficits.\n                <\/jats:p>","DOI":"10.64898\/2026.09.22.753612","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:40:15Z","timestamp":1790242815000},"source":"Crossref","is-referenced-by-count":0,"title":["Gene therapy with doxycycline-controlled expression of human Kv1.1 reduces neuronal excitability and increases sociability of\n                  <i>Scn2a<\/i>\n                  -deficient mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1404-5694","authenticated-orcid":false,"given":"Brody A.","family":"Deming","sequence":"first","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University"},{"name":"Purdue Institute for 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