Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

Recent large-scale genomic studies have revealedSCN2Aas one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability.SCN2Aencodes for voltage-gated sodium channel isoform 1.2 (Nav1.2), which is mainly expressed in the central nervous system and responsible for the propagation of neuronal action potentials. Homozygous knockout (null) ofScn2ais perinatal lethal, whereas heterozygous knockout ofScn2aresults in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction ofScn2aexpression, we characterized aScn2adeficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-functionSCN2Adisorders. This model produces viable homozygous mice (Scn2agtKO/gtKO) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. AlthoughScn2agtKO/gtKOadult mice possess normal olfactory, taste, hearing, and mechanical sensitivity, they have decreased thermal and cold tolerance. Innate behaviors are profoundly impaired including impaired nesting, marble burying, and mating. These mice also have increased food and water intake with subsequent increases in fecal excretion of more but smaller fecal boli. This novelScn2agene trap knockout mouse thus provides a unique model to study pathophysiology associated withScn2adeficiency.