Sex differences in seizure presentation in Dravet syndrome model mice,Scn1a+/-

Abstract

AbstractDravet syndrome (DS) is an epileptic encephalopathy mostly due to haploinsufficiency of theSCN1Avoltagegated sodium channel subunit. Disease presentation (i.e., severe seizures and early life mortality) is highly recapitulated in mice haploinsufficient inScn1a(Scn1a+/-). However, phenotypic characterization inScn1a+/-mice in a sex and temporal manner is limited. Given the reliance of mouse models for studying disease pathophysiology and for the development of novel treatments, we tested whether mortality and seizure morbidity differed among young and adult male and femaleScn1a+/-animals in the F1 hybrid C57×129S6 background. We found increased mortality in femaleScn1a+/-mice regardless of age compared to their male counterparts (n = 120-125 mice/sex;p < 0.05). Interestingly, long-term video EEG recordings revealed the opposite for morbidity as seizure frequency and severity were escalated in adult maleScn1a+/-animals (n = 21-30 mice/sex;p < 0.05orp < 0.01). Adult femaleScn1a+/-mice, however, are more hyperactive (p < 0.05), which could be related to sleep impairment and contribute to the increased mortality despite decreased seizure morbidity. Overall, the phenotypic presentation ofScn1a+/-mice is sex-dependent and may have translational implications for therapeutic drug discovery and basic biology understanding in DS.Short SummarySex differences in mortality and seizure morbidity are discovered inScn1ahaploinsufficient mice,Scn1a+/-, which faithfully model the epileptic encephalopathy disorder, Dravet syndrome (DS). FemaleScn1a+/-mice die more across all ages, whereas adult maleScn1a+/-mice have more seizures that are of greater severity. Hyperactivity, as a proxy for sleep disruption, may contribute to the increased mortality in femaleScn1a+/-mice despite decreased seizure incidence and severity. These sex-specific findings may have considerable impact in therapeutic discovery and development for DS and otherSCN1A-related disorders.