title: Early-life febrile seizures worsen adult phenotypes in Scn1a mutants.
abstract: Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Nav1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). Patients with SCN1A mutations often experience prolonged early-life febrile seizures (FSs), raising the possibility that these events may influence epileptogenesis and lead to more severe adult phenotypes. To test this hypothesis, we subjected 21-23-day-old mice expressing the human SCN1A GEFS+ mutation R1648H to prolonged hyperthermia, and then examined seizure and behavioral phenotypes during adulthood. We found that early-life FSs resulted in lower latencies to induced seizures, increased severity of spontaneous seizures, hyperactivity, and impairments in social behavior and recognition memory during adulthood. Biophysical analysis of brain slice preparations revealed an increase in epileptiform activity in CA3 pyramidal neurons along with increased action potential firing, providing a mechanistic basis for the observed worsening of adult phenotypes. These findings demonstrate the long-term negative impact of early-life FSs on disease outcomes. This has important implications for the clinical management of this patient population and highlights the need for therapeutic interventions that could ameliorate disease progression.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30022, USA; Department of Biology, Agnes Scott College, Atlanta, GA 30030, USA.
authors.forename: Stacey B B
authors.initials: SBB
authors.lastname: Dutton
authors.affiliation: Departments of Microbiology & Molecular Genetics and Anatomy & Neurobiology, University of California, Irvine, CA 92697, USA.
authors.forename: Karoni
authors.initials: K
authors.lastname: Dutt
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 Neurology, Emory University, Atlanta, GA 30022, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Helmers
authors.affiliation: Departments of Microbiology & Molecular Genetics and Anatomy & Neurobiology, University of California, Irvine, CA 92697, USA.
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: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000235:genetics; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D005481:Flurothyl / Q000633:toxicity; D006624:Hippocampus / Q000473:pathology; D006639:Histidine / Q000235:genetics; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D003294:Seizures, Febrile / Q000150:complications* / Q000209:etiology / Q000235:genetics* / Q000473:pathology
chemical_list: D003292:Convulsants; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; D006639:Histidine; D001120:Arginine; D005481:Flurothyl
keywords: Epilepsy; Febrile seizures; GEFS+; Na(v)1.1; SCN1A