title: Neuronal hyperexcitability in a mouse model ofSCN8Aepileptic encephalopathy.
abstract: Patients with early infantile epileptic encephalopathy (EIEE) experience severe seizures and cognitive impairment and are at increased risk for sudden unexpected death in epilepsy (SUDEP). EIEE13 [Online Mendelian Inheritance in Man (OMIM) # 614558] is caused by de novo missense mutations in the voltage-gated sodium channel geneSCN8AHere, we investigated the neuronal phenotype of a mouse model expressing the gain-of-functionSCN8Apatient mutation, p.Asn1768Asp (Nav1.6-N1768D). Our results revealed regional and neuronal subtype specificity in the effects of the N1768D mutation. Acutely dissociated hippocampal neurons fromScn8aN1768D/+mice showed increases in persistent sodium current (INa) density in CA1 pyramidal but not bipolar neurons. In CA3,INa,Pwas increased in both bipolar and pyramidal neurons. Measurement of action potential (AP) firing inScn8aN1768D/+pyramidal neurons in brain slices revealed early afterdepolarization (EAD)-like AP waveforms in CA1 but not in CA3 hippocampal or layer II/III neocortical neurons. The maximum spike frequency evoked by depolarizing current injections inScn8aN1768D/+CA1, but not CA3 or neocortical, pyramidal cells was significantly reduced compared with WT. Spontaneous firing was observed in subsets of neurons in CA1 and CA3, but not in the neocortex. The EAD-like waveforms ofScn8aN1768D/+CA1 hippocampal neurons were blocked by tetrodotoxin, riluzole, and SN-6, implicating elevated persistentINaand reverse mode Na/Ca exchange in the mechanism of hyperexcitability. Our results demonstrate thatScn8aplays a vital role in neuronal excitability and provide insight into the mechanism and future treatment of epileptogenesis in EIEE13.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Lopez-Santiago
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Jacy L
authors.initials: JL
authors.lastname: Wagnon
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hull
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Frasier
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Heather A
authors.initials: HA
authors.lastname: O'Malley
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109.|Department of Neurology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109; lisom@umich.edu.|Department of Neurology, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Lori L
authors.identifier: 0000-0002-9479-6729
authors.initials: LL
authors.lastname: Isom
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D019943:Amino Acid Substitution; D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019782:Riluzole / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013036:Spasms, Infantile / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013779:Tetrodotoxin / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; D001593:Benzyl Compounds; D062557:NAV1.6 Voltage-Gated Sodium Channel; C491046:Scn8a protein, mouse; D026941:Sodium Channel Blockers; D053778:Thiazolidines; D013779:Tetrodotoxin; D019782:Riluzole
keywords: Na/Ca exchange; action potential; epilepsy; mouse model; sodium channel