Modeling SCN2A Deficiency in Mice

Abstract

Encoded by the gene SCN2A (Scn2a in mice), Nav1.2 sodium channels propagate action potentials as the main form of communication in the brain, especially during development. When the SCN2A gene becomes disrupted by mutation, the phenotypic results range from epilepsy to autism in humans. A mouse was selected to model the effects of SCN2A-related neurodevelopmental disorders and examine the efficacy of potential therapies. A gene trap reduced Scn2a gene expression and increased survivability past the perinatal state, unlike a complete Scn2a knockout. A functional Scn2a transcript was produced at levels of 29 ± 4% in homozygous (HOM) gene-trap mice, compared to 100% expression in wild-type (WT) mice. HOM mice did not mate, so heterozygous (HET) mice had to be used for breeding. Mendelian genetics dictates crossing two HETs gives a 1:2:1 probability that offspring could be either HOM, HET, or WT. Therefore, each mouse pup was genotyped with PCR, and a final Mendelian ratio was calculated to determine if the litters followed the theoretical 1:2:1 pattern. A chi-square goodness of fit test was performed and concluded the results were not significant (p = 0.0676), showing the data followed the theoretical 1:2:1 ratio at a >95% confidence interval. Only litters with at least one HOM were included to reduce bias from inconsistent genotyping. The most frequent genotyping issues were maintaining consistent DNA/elution buffer concentrations during extraction and streaking on the electrophoresis gel. Overall, the HOM gene-trap mice will continue to serve as a model for testing new therapies for SCN2A-related neurodevelopmental disorders.