Abstracts

Rationale: Dravet syndrome is a rare genetic form of drug-refractory epilepsy with no effective therapies. Comorbidities include cognitive impairment, behavioral abnormalities including stereotypies, hyperactivity, attention deficits and impaired social interactions, motor problems, sleep disorders, and premature death. Existing Dravet mouse models are not ideal for therapy development projects for various reasons. Some have early onset lethality that prevents shipping and sharing of mice. Most are not widely available for drug testing efforts due to legal restrictions. To address this need, we have developed a novel inducible model that is viable and available for drug development projects with a no-cost license: B6(Cg)-Scn1atm1.1Dsf/J (#26133). Methods: We used homologous recombination to engineer an allele of the mouse Scn1a gene that is normal until exposed to cre activity, when the floxed wild-type exon 26 is deleted and an engineered exon 26 carrying the A1783V patient mutation is expressed. Results: As verified by sequencing of mRNA, mutant Scn1a expression can be induced by mating to the appropriate cre-expressing strain. Consistent with reports from other Dravet mouse models, inducing expression of the A1783V mutation in heterozygotes (HET) using a ubiquitous cre on a pure C57BL/6J genetic background resulted in ~90% lethality at ~ 3 weeks of age, while using a ubiquitous cre on a 129S1 genetic background (129S1/Sv-Hprttm1(CAG-cre)Mnn/J (#4302) allows ~50% survival into adulthood and behavioral phenotyping. Initial behavioral characterization of adult mice (age 8-12 weeks; n=8-14 per sex per genotype) revealed spontaneous seizure activity, hyperactivity, and stereotypical behaviors in male and female HET mice that were not observed in WT littermate controls. Two-way repeated measures ANOVA revealed significant increases in distance traveled in the open field in male and female HET mice, relative to sex-matched WT controls indicative of hyperactivity (p < 0.01 and p < 0.001 within sex for males and females respectively, Figure 1). Analysis of repetitive jumping behavior (10 min video recording) revealed a striking behavioral phenotype with significant increases in number of jumps in male and female HET mice relative to sex-matched WT controls (p < 0.01 within sex; Figure 2). Conclusions: We have created and characterized an inducible model of Dravet, such that un-induced mice are healthy and can easily be distributed, that captures many of the characteristic patient phenotypes. We expect that making this model and corresponding cre-expressing mice lines easily available will facilitate its use as a drug screening platform and the development of effective therapies for Dravet syndrome. Funding: Funded by the Dravet Syndrome Foundation Spain with support from the Swiss Dravet Syndrome Association, Dravet-Syndrom e.V., Stichting Dravetsyndroom NL/VL, Associazione Italiana Sindrome di Dravet Onlus and the Gruppo Famiglie Dravet Associazione Onlus.