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Characterization of a gene-trap knockout mouse model of Scn2a encoding voltage-gated sodium channel Nav1.2

By Muriel Eaton, Jingliang Zhang, Zhixiong Ma, Anthony C Park, Emma Lietzke, ChloƩ Maricela Romero, Yushuang Liu, Emily Rose Coleman, Xiaoling Chen, Tiange Xiao, Zhuo Huang, William C. Skarnes, Wendy A. Koss, Yang Yang

Posted 23 Jun 2020
bioRxiv DOI: 10.1101/2020.06.23.150367

Recent large-scale genomic studies have revealed SCN2A as one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability. SCN2A encodes 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) of Scn2a is perinatal lethal, whereas heterozygous knockout of Scn2a results in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction of Scn2a expression, we characterized a Scn2a deficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-function SCN2A disorders. This model produces viable homozygous mice (Scn2agtKO/gtKO) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. Although Scn2agtKO/gtKO adult 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 novel Scn2a gene trap knockout mouse thus provides a unique model to study pathophysiology associated with Scn2a deficiency. ### Competing Interest Statement The authors have declared no competing interest.

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