Abstracts

Rationale: Voltage-gated sodium channels (VGSCs), responsible for the initiation and propagation of action potentials, play an important role in genetically acquired forms of epilepsy. For example, mutations in the VGSCs SCN1A, SCN2A, and SCN8A are being identified in an increasing number of epilepsy disorders. Less is known, however, about the role of SCN3A and SCN9A in epilepsy. To date, a small number of SCN3A mutations have been found in patients with cryptogenic pediatric partial epilepsy. SCN9A mutations have been implicated in febrile seizures and as a possible genetic modifier of SCN1A. We used two mouse models to test the hypotheses: 1) that loss of SCN3A will increase seizure susceptibility and alter behavior and 2) that SCN9A will genetically modify SCN1A, leading to a more severe phenotype. Methods: To test the first hypothesis, 5-8 week old heterozygous loss-of-function Scn3a mutants (Scn3a^+/-; n = 58) and wild type (WT) littermates (n = 61) were administered the pro-convulsant flurothyl and seizure latencies were determined. Seizure resistance to electrical stimulation, utilizing the 6Hz seizure induction paradigm, was also determined in these mice (Scn3a^+/-: n = 10-11; WT: n = 9-12). Scn3a^+/- (n = 8-11) and WT mice (n = 8-9) underwent behavioral analyses to characterize locomotor activity, motor coordination, anxiety, depression, social behavior, learning, and memory. To test the second hypothesis, mice with human SCN9A mutation N641Y (NY) were crossed with mice expressing human mutation SCN1A R1648H (RH) to produce four genotypes: WT (n = 10), NY/+ (n = 14), RH/+ (n = 17), and double heterozygous mutants NY/RH (n = 15), and latencies to flurothyl-induced seizures were determined. Results: Scn3a^+/- mice showed significantly reduced latencies to flurothyl-induced seizures (p < 0.05) compared to WT littermates. Based on the 6 Hz paradigm, the CC₅₀ (the convulsive current at which 50% of each genotype seized) was significantly lower for Scn3a^+/- mice compared to WT (95% CI for Scn3a^+/- [19.826-25.386]; 95% CI for WT [26.716-38.439]). Scn3a^+/- mutants also exhibited significantly impaired locomotor activity and a decreased latency to fall in the rotarod assay (p < 0.05). No significant difference in latency to flurothyl-induced seizures was observed between the NY/RH mutants and any of the other three genotypes. Conclusions: We have demonstrated that