Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

• Type of Material: Article
• Authors: Stacey B. B. Dutton, Emory University; Karoni Dutt, University of California Irvine; Ligia A. Papale, Emory University; Sandra Helmers, Emory University; Alan L. Goldin, University of California Irvine; Andrew Escayg, Emory University
• Language: English
• Date: 2017-07-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.expneurol.2017.03.026
• Title of Journal or Parent Work: Experimental Neurology
• ISSN: 0014-4886
• Volume: 293
• Start Page: 159
• End Page: 171
• Grant/Funding Information: This research was supported by grants from NIH to AE (NS072221), ALG (NS048336), AE/ALG (NS065187) and an NIH/NIGMS IRACDA grant to SD (K12 GM000680).
• Keywords: Neurosciences; STATUS EPILEPTICUS; Science & Technology; GABAERGIC SYNAPTIC-TRANSMISSION; SCN1A; DRAVET-SYNDROME; HYPERTHERMIA-INDUCED SEIZURES; Neurosciences & Neurology; Na(v)1.1; SEVERE MYOCLONIC EPILEPSY; MOUSE MODEL; Febrile seizures; Life Sciences & Biomedicine; AUTISTIC-LIKE BEHAVIOR; Epilepsy; LONG-TERM; TEMPORAL-LOBE EPILEPSY; RAT HIPPOCAMPUS; GEFS
• Research Categories: Biology, General; Biology, Microbiology

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.