Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABA A receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFSϩ). A novel mutation, R859C, in the Na v 1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFSϩ. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Na v 1.1 channel ␣ subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Na v 1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFSϩ sodium channel mutations, which have changes predicted to increase neuronal firing.

Understanding the role of SCN8A in epilepsy and behavior is critical in light of recently identified human SCN8A epilepsy mutations. We have previously demonstrated that Scn8amed and Scn8amed-jo mice carrying mutations in the Scn8a gene display increased resistance to flurothyl and kainic acid-induced seizures; however, they also exhibit spontaneous absence seizures. To further investigate the relationship between altered SCN8A function and epilepsy, we introduced the SCN1A-R1648H mutation, identified in a family with generalized epilepsy with febrile seizures plus (GEFS+), into the corresponding position (R1627H) of the mouse Scn8a gene. Heterozygous R1627H mice exhibited increased resistance to some forms of pharmacologically and electrically induced seizures and the mutant Scn8a allele ameliorated the phenotype of Scn1a-R1648H mutants. Hippocampal slices from heterozygous R1627H mice displayed decreased bursting behavior compared to wild-type littermates. Paradoxically, at the homozygous level, R1627H mice did not display increased seizure resistance and were susceptible to audiogenic seizures. We furthermore observed increased hippocampal pyramidal cell excitability in heterozygous and homozygous Scn8a-R1627H mutants, and decreased interneuron excitability in heterozygous Scn8a-R1627H mutants. These results expand the phenotypes associated with disruption of the Scn8a gene and demonstrate that an Scn8a mutation can both confer seizure protection and increase seizure susceptibility.