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Homozygous knockout (null) of <jats:italic>Scn2a<\/jats:italic> in mice is perinatal lethal, whereas heterozygous knockout of <jats:italic>Scn2a<\/jats:italic> (<jats:italic>Scn2a<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup>) results in mild behavior abnormalities. The Na<jats:sub>v<\/jats:sub>1.2 expression level in <jats:italic>Scn2a<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> mice is reported to be around 50\u201360% of the wild\u2010type (WT) level, which indicates that a close to 50% reduction of Na<jats:sub>v<\/jats:sub>1.2 expression may not be sufficient to lead to major behavioral phenotypes in mice. To overcome this barrier, we characterized a novel mouse model of severe <jats:italic>Scn2a<\/jats:italic> deficiency using a targeted gene\u2010trap knockout (gtKO) strategy. This approach produces viable homozygous mice (<jats:italic>Scn2a<\/jats:italic><jats:sup><jats:italic>gtKO\/gtKO<\/jats:italic><\/jats:sup>) that can survive to adulthood, with about a quarter of Na<jats:sub>v<\/jats:sub>1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in <jats:italic>Scn2a<\/jats:italic><jats:sup><jats:italic>gtKO\/gtKO<\/jats:italic><\/jats:sup> mice. Notably, <jats:italic>Scn2a<\/jats:italic><jats:sup><jats:italic>gtKO\/gtKO<\/jats:italic><\/jats:sup> mice have a significantly decreased center duration compared to WT in the open field test, suggesting anxiety\u2010like behaviors in a novel, open space. These mice also have decreased thermal and cold tolerance. Additionally, <jats:italic>Scn2a<\/jats:italic><jats:sup><jats:italic>gtKO\/gtKO<\/jats:italic><\/jats:sup> mice have increased fix\u2010pattern exploration in the novel object exploration test and a slight increase in grooming, indicating a detectable level of repetitive behaviors. They bury little to no marbles and have decreased interaction with novel objects. These <jats:italic>Scn2a<\/jats:italic> gene\u2010trap knockout mice thus provide a unique model to study pathophysiology associated with severe <jats:italic>Scn2a<\/jats:italic> deficiency.<\/jats:p>","DOI":"10.1111\/gbb.12725","type":"journal-article","created":{"date-parts":[[2020,12,25]],"date-time":"2020-12-25T10:11:58Z","timestamp":1608891118000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Generation and basic characterization of a gene\u2010trap knockout mouse model of <i>Scn2a<\/i> with a substantial reduction of voltage\u2010gated sodium channel Na<sub>v<\/sub>1.2 expression"],"prefix":"10.1111","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-1214","authenticated-orcid":false,"given":"Muriel","family":"Eaton","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology College of Pharmacy, Purdue University  West Lafayette Indiana 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