{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:47:21Z","timestamp":1790743641831,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,17]]},"group-title":"Neuroscience","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["R25 NS130966"],"award-info":[{"award-number":["R25 NS130966"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P50 HD103556"],"award-info":[{"award-number":["P50 HD103556"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DOD AR220030"],"award-info":[{"award-number":["DOD AR220030"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Autism spectrum disorder is a neurodevelopmental disorder with both genetic and environmental contributors.\n                  <jats:italic>SCN2A<\/jats:italic>\n                  , the gene which encodes the alpha subunit of the voltage-gated sodium channel Na\n                  <jats:sub>v<\/jats:sub>\n                  1.2, is a known monogenetic risk factor for autism spectrum disorder. The cerebellum is frequently implicated in autism spectrum disorder and other neurodevelopmental disorders but has largely been unexplored in relation to\n                  <jats:italic>SCN2A<\/jats:italic>\n                  variants, especially from a developmental perspective. Na\n                  <jats:sub>v<\/jats:sub>\n                  1.2 is highly expressed within the cerebellum, specifically within cerebellar granule neurons, where it helps to drive action potential generation and propagation. Cerebellar granule neuron activity and maturation is crucial for shaping the development and morphology of the rest of the cerebellar cortex. Here we investigated early-postnatal cerebellar development in two mouse models carrying patient-derived\n                  <jats:italic>SCN2A<\/jats:italic>\n                  premature termination codon variants,\n                  <jats:italic>Scn2a-<\/jats:italic>\n                  p.Y84X and -p.R1627X. Overall, both\n                  <jats:italic>Scn2a<\/jats:italic>\n                  premature termination codon variant mouse lines displayed largely normal physical development and unaffected non-cerebellar developmental milestones.\n                  <jats:italic>\n                    Scn2a\n                    <jats:sup>Y84X\/+<\/jats:sup>\n                  <\/jats:italic>\n                  mice, but not\n                  <jats:italic>\n                    Scn2a\n                    <jats:sup>R1627X\/+<\/jats:sup>\n                  <\/jats:italic>\n                  mice, demonstrated alterations in cerebellar-driven motor behaviors, specifically faster performance in the surface righting reflex and cliff avoidance compared to wildtype littermates. Coinciding with the behavioral findings,\n                  <jats:italic>Scn2a<\/jats:italic>\n                  variants had divergent and age-dependent effects on cerebellar glutamatergic presynaptic marker expression, indicating that some, but not all,\n                  <jats:italic>Scn2a<\/jats:italic>\n                  premature termination codons impair glutamatergic synapse development. Both\n                  <jats:italic>Scn2a<\/jats:italic>\n                  variants exhibited changes to cerebellar cytoarchitecture, such as reductions in Purkinje cell density and soma size, which was more prominent in\n                  <jats:italic>\n                    Scn2a\n                    <jats:sup>Y84X\/+<\/jats:sup>\n                  <\/jats:italic>\n                  mice, and faster migration of cerebellar granule neurons from the external granule layer to the internal, indicating a possible shift in the timing of cerebellar maturation. Our results situate the cerebellum as an early site for\n                  <jats:italic>SCN2A<\/jats:italic>\n                  pathophysiology and establish that cerebellar consequences of\n                  <jats:italic>SCN2A<\/jats:italic>\n                  premature termination codon variants may be position- and age-dependent, suggesting that influences beyond simple heterozygous loss of Nav1.2 drive phenotypes. Our characterization of how\n                  <jats:italic>Scn2a<\/jats:italic>\n                  premature termination codon variants differentially impair cerebellar development may help explain the heterogeneity of clinical presentations of\n                  <jats:italic>SCN2A<\/jats:italic>\n                  loss of function variants and potentially inform upon the timing of therapeutic intervention.\n                <\/jats:p>","DOI":"10.64898\/2026.09.13.751275","type":"posted-content","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:25:18Z","timestamp":1789647918000},"source":"Crossref","is-referenced-by-count":1,"title":["Developmental Cerebellar Pathology in Mouse Models of\n                  <i>SCN2A<\/i>\n                  Premature Termination Codon Variants"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1574-2838","authenticated-orcid":false,"given":"Katelin E.J","family":"Scott","sequence":"first","affiliation":[{"name":"Interdisciplinary Neuroscience Graduate Program, Iowa City, IA, USA"},{"name":"Psychiatry Department, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Gorter","sequence":"additional","affiliation":[{"name":"Psychiatry Department, Iowa City, IA, USA"},{"name":"iDREAM, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alayna","family":"Mull","sequence":"additional","affiliation":[{"name":"Psychiatry Department, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0650-1119","authenticated-orcid":false,"given":"Patrick","family":"Breheny","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7975-2744","authenticated-orcid":false,"given":"Chris A.","family":"Ahern","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8139-2303","authenticated-orcid":false,"given":"Aislinn J.","family":"Williams","sequence":"additional","affiliation":[{"name":"Psychiatry Department, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092110351483000_2026.09.13.751275v1.1","unstructured":"CDC. 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