title: Scn1a dysfunction alters behavior but not the effect of stress on seizure response.
abstract: Mutations in the voltage-gated sodium channel gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition, dysfunction in SCN1A is increasingly being linked to neuropsychiatric abnormalities, social deficits and cognitive disabilities. We have previously reported that mice heterozygous for the SCN1A R1648H mutation identified in a GEFS+ family have infrequent spontaneous seizures, increased susceptibility to chemically and hyperthermia-induced generalized seizures and sleep abnormalities. In this study, we characterized the behavior of heterozygous mice expressing the SCN1A R1648H mutation (Scn1a(RH/+)) and the effect of stress on spontaneous and induced seizures. We also examined the effect of the R1648H mutation on the hypothalamic-pituitary-adrenal (HPA) axis response. We confirmed our previous finding that Scn1a(RH/+) mutants are hyperactive, and also identified deficits in social behavior, spatial memory, cued fear conditioning, pre-pulse inhibition and risk assessment. Furthermore, while exposure to a stressor did increase seizure susceptibility, the effect seen in the Scn1a(RH/+) mutants was similar to that seen in wild-type littermates. In addition, Scn1a dysfunction does not appear to alter HPA axis function in adult animals. Our results suggest that the behavioral abnormalities associated with Scn1a dysfunction encompass a wider range of phenotypes than previously reported and factors such as stress exposure may alter disease severity in patients with SCN1A mutations.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA.|Department of Biology, Clayton State University, Morrow, GA.
authors.forename: N T
authors.initials: NT
authors.lastname: Sawyer
authors.affiliation: Byrdine F. Lewis School of Nursing and Health Professions, Georgia State University, Atlanta, GA.
authors.forename: A W
authors.initials: AW
authors.lastname: Helvig
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA.
authors.forename: C D
authors.initials: CD
authors.lastname: Makinson
authors.affiliation: Departments of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH.|Department of Neuroscience, School of Nursing, Case Western Reserve University, Cleveland, OH.
authors.forename: M J
authors.initials: MJ
authors.lastname: Decker
authors.affiliation: Department of Physiology, Emory University, Atlanta, GA, USA.|Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Neigh
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA.
authors.forename: A
authors.initials: A
authors.lastname: Escayg
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D004569:Electroencephalography; D005260:Female; D006579:Heterozygote; D007030:Hypothalamo-Hypophyseal System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D010641:Phenotype; D010913:Pituitary-Adrenal System; D012640:Seizures / Q000235:genetics* / Q000378:metabolism*; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse
keywords: Behavior; Scn1a; epilepsy; hyperactivity; sodium channel; stress