Generation and basic characterization of a gene‐trap knockout mouse model of Scn2a with a substantial reduction of voltage‐gated sodium channel Na v 1.2 expression

Large‐scale genetic studies revealed SCN2A as one of the most frequently mutated genes in patients with neurodevelopmental disorders. SCN2A encodes for the voltage‐gated sodium channel isoform 1.2 (Na v 1.2) expressed in the neurons of the central nervous system. Homozygous knockout (null) of Scn2a in mice is perinatal lethal, whereas heterozygous knockout of Scn2a ( Scn2a +/− ) results in mild behavior abnormalities. The Na v 1.2 expression level in Scn2a +/− mice is reported to be around 50–60% of the wild‐type (WT) level, which indicates that a close to 50% reduction of Na v 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 Scn2a deficiency using a targeted gene‐trap knockout (gtKO) strategy. This approach produces viable homozygous mice ( Scn2a gtKO/gtKO ) that can survive to adulthood, with about a quarter of Na v 1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in Scn2a gtKO/gtKO mice. Notably, Scn2a gtKO/gtKO mice have a significantly decreased center duration compared to WT in the open field test, suggesting anxiety‐like behaviors in a novel, open space. These mice also have decreased thermal and cold tolerance. Additionally, Scn2a gtKO/gtKO mice have increased fix‐pattern 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 Scn2a gene‐trap knockout mice thus provide a unique model to study pathophysiology associated with severe Scn2a deficiency.