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A multi-disciplinary collaboration generated a novel mouse model (C57BL\/6-\n                  <jats:italic>\n                    Kcnt1\n                    <jats:sup>em1Bryd<\/jats:sup>\n                  <\/jats:italic>\n                  ) carrying the G269S variant, corresponding to human G288S, located within the coding region of the channel pore. Network excitability of cultured cortical neurons from\n                  <jats:italic>Kcnt1<\/jats:italic>\n                  <jats:sup>+\/G269S<\/jats:sup>\n                  exhibited sustained hyperexcitability and hypersynchronous bursting while\n                  <jats:italic>Kcnt1<\/jats:italic>\n                  <jats:sup>G269S\/G269S<\/jats:sup>\n                  neurons showed early excessive bursting followed by network collapse, suggesting excitotoxicity.\n                  <jats:italic>Kcnt1<\/jats:italic>\n                  <jats:sup>+\/G269S<\/jats:sup>\n                  displayed poor motor coordination, erratic breathing, and increased apneas. Critically,\n                  <jats:italic>Kcnt1<\/jats:italic>\n                  <jats:sup>+\/G269S<\/jats:sup>\n                  were more susceptible to thermal-induced seizures in early life. In summary, these data: (i) provide a novel mouse model of KCNT1-related epilepsy, (ii) provide strong\n                  <jats:italic>in vitro<\/jats:italic>\n                  evidence of neuronal hyperexcitability, (iii) illustrate early-life seizures as a functional outcome measure, and (iv) lay the groundwork for future analysis of neural activity\n                  <jats:italic>in vivo<\/jats:italic>\n                  and modeling circuit level dynamics\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in silico<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Gain-of-function mutations in the sodium-gated potassium channel KCNT1 have been linked to pediatric epilepsy of varying severity. The human\n                    <jats:italic>KCNT1<\/jats:italic>\n                    variant G288S (G269S in mice) is linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), Epilepsy of Infancy with Migrating Focal Seizures (EIMFS), and other severe developmental epileptic encephalopathies. There are currently no therapeutics to prevent the progression of\n                    <jats:italic>KCNT1<\/jats:italic>\n                    -related epilepsy, therefore, the scientific community requires a novel mouse model that is well characterized,\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo,<\/jats:italic>\n                    to screen and assess targeted therapeutics. Herein, we engineered a novel mouse to assess developmental and adult phenotypes resulting from the G288S\/G269S variant,\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , to advance translation toward therapeutic testing for individuals with\n                    <jats:italic>KCNT1<\/jats:italic>\n                    -related epilepsy.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.22.666003","type":"posted-content","created":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T06:05:10Z","timestamp":1753509910000},"source":"Crossref","is-referenced-by-count":1,"title":["Novel Gain of Function Mouse Model of KCNT1-Related Epilepsy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6669-1233","authenticated-orcid":false,"given":"Sarah 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