title: An Scn1a epilepsy mutation in Scn8a alters seizure susceptibility and behavior.
abstract: 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 Scn8a(med) and Scn8a(med-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.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30022, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Makinson
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Karoni
authors.initials: K
authors.lastname: Dutt
authors.affiliation: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30022, USA.
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Papale
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30022, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Shankar
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Barela
authors.affiliation: Department of Biology, Emory University, Atlanta, GA 30022, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA 92697, USA. Electronic address: agoldin@uci.edu.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Goldin
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30022, USA. Electronic address: aescayg@emory.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001933:Brain Stem / Q000378:metabolism / Q000503:physiopathology; D004198:Disease Susceptibility; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism*; D012640:Seizures / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; C491046:Scn8a protein, mouse
keywords: Audiogenic seizure; Dravet syndrome; GEFS+; Interneuron; Na(v)1.1; Na(v)1.6; Sodium channel; Voltage sensor