{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:11:51Z","timestamp":1790665911781,"version":"4.1.0"},"posted":{"date-parts":[[2025,6,6]]},"group-title":"Neuroscience","reference-count":97,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"The National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,6]]},"abstract":"Abstract<\/jats:title>\n \n Mutations in the voltage-gated sodium channel gene\n SCN2A<\/jats:italic>\n , which encodes the Na\n V<\/jats:sub>\n 1.2 channel, cause severe epileptic seizures. Patients with\n SCN2A<\/jats:italic>\n loss-of-function (LoF) mutations, such as protein-truncating mutations, often experience later-onset and drug-resistant epilepsy, highlighting an urgent unmet clinical need for new therapies. We previously developed a gene-trap\n Scn2a<\/jats:italic>\n (\n \n Scn2a\n gt\/gt<\/jats:sup>\n <\/jats:italic>\n ) mouse model with a global Na\n V<\/jats:sub>\n 1.2 reduction in the widely used C57BL\/6N (B6) strain. Although these mice display multiple behavioral abnormalities, EEG recordings indicated only mild epileptiform discharges, possibly attributable to the seizure-resistant characteristics associated with the B6 strain. To enhance the epileptic phenotype, we derived congenic\n \n Scn2a\n gt\/gt<\/jats:sup>\n <\/jats:italic>\n mice in the seizure-susceptible DBA\/2J (D2J) strain. Notably, we found that these mice exhibit prominent spontaneous absence seizures, marked by both short and long spike-wave discharges (SWDs). Restoring Na\n V<\/jats:sub>\n 1.2 expression in adult mice substantially reduced their SWDs, suggesting the possibility of\n SCN2A<\/jats:italic>\n gene replacement therapy during adulthood. RNA sequencing revealed significant alterations in gene expression in the\n \n Scn2a\n gt\/gt<\/jats:sup>\n <\/jats:italic>\n mice, in particular a broad downregulation of voltage-gated potassium channel (K\n V<\/jats:sub>\n ) genes, including K\n V<\/jats:sub>\n 1.1. The reduction of K\n V<\/jats:sub>\n 1.1 expression was further validated in human cerebral organoids with\n SCN2A<\/jats:italic>\n deficiency, highlighting K\n V<\/jats:sub>\n 1.1 as a promising therapeutic target for refractory seizures associated with\n SCN2A<\/jats:italic>\n dysfunction. Importantly, delivery of exogenous human K\n V<\/jats:sub>\n 1.1 expression via adeno-associated virus (AAV) in D2J\n \n Scn2a\n gt\/gt<\/jats:sup>\n <\/jats:italic>\n mice substantially reduced absence seizures. Together, these findings underscore the influence of mouse strain on seizure severity and highlight the potential of targeted gene therapies for treating\n SCN2A<\/jats:italic>\n deficiency-related epilepsies.\n <\/jats:p>\n \n Graphical abstract<\/jats:title>\n \n \n <\/jats:fig>\n \n In brief<\/jats:title>\n \n Scn2a<\/jats:italic>\n deficiency leads to absence seizures in D2J mice and neuronal hyperexcitability with compensatory K\n V<\/jats:sub>\n reduction; restoring Na\n V<\/jats:sub>\n 1.2 or introducing human K\n V<\/jats:sub>\n 1.1 reduces seizure burden.\n <\/jats:p>\n <\/jats:sec>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n Scn2a<\/jats:italic>\n deficiency induces robust absence seizures in the DBA\/2J but not the C57BL\/6N strain.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Cortical neurons in adult DBA\/2J mice with\n Scn2a<\/jats:italic>\n deficiency exhibit intrinsic hyperexcitability.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Severe\n Scn2a<\/jats:italic>\n deficiency leads to downregulation of multiple potassium channel genes.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Genetic restoration of Na\n V<\/jats:sub>\n 1.2 expression alleviates spike-wave discharges (SWDs).\n <\/jats:p>\n <\/jats:list-item>\n \n \n AAV-mediated human K\n V<\/jats:sub>\n 1.1 delivery substantially reduced absence seizures, demonstrating the therapeutic potential of targeted gene therapy.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>","DOI":"10.1101\/2025.06.03.657652","type":"posted-content","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T20:35:15Z","timestamp":1749242115000},"source":"Crossref","is-referenced-by-count":1,"title":["Gene therapies alleviate absence epilepsy associated with\n Scn2a<\/i>\n deficiency in DBA\/2J mice"],"prefix":"10.64898","author":[{"given":"Zaiyang","family":"Zhang","sequence":"first","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 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