title: Cardiac arrhythmia in a mouse model of sodium channelSCN8Aepileptic encephalopathy.
abstract: Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel geneSCN8A, encoding the sodium channel Nav1.6, result in EIEE13 (OMIM 614558), which has a 10% risk of SUDEP. Here, we investigated the cardiac phenotype of a mouse model expressing the gain of function EIEE13 patient mutation p.Asn1768Asp inScn8a(Nav1.6-N1768D). We testedScn8aN1768D/+mice for alterations in cardiac excitability. We observed prolongation of the early stages of action potential (AP) repolarization in mutant myocytes vs. controls.Scn8aN1768D/+myocytes were hyperexcitable, with a lowered threshold for AP firing, increased incidence of delayed afterdepolarizations, increased calcium transient duration, increased incidence of diastolic calcium release, and ectopic contractility. Calcium transient duration and diastolic calcium release in the mutant myocytes were tetrodotoxin-sensitive. A selective inhibitor of reverse mode Na/Ca exchange blocked the increased incidence of diastolic calcium release in mutant cells.Scn8aN1768D/+mice exhibited bradycardia compared with controls. This difference in heart rate dissipated after administration of norepinephrine, and there were no differences in heart rate in denervated ex vivo hearts, implicating parasympathetic hyperexcitability in theScn8aN1768D/+animals. When challenged with norepinephrine and caffeine to simulate a catecholaminergic surge,Scn8aN1768D/+mice showed ventricular arrhythmias. Two of three mutant mice under continuous ECG telemetry recording experienced death, with severe bradycardia preceding asystole. Thus, in addition to central neuron hyperexcitability,Scn8aN1768D/+mice have cardiac myoycte and parasympathetic neuron hyperexcitability. Simultaneous dysfunction in these systems may contribute to SUDEP associated with mutations ofScn8a.
authors: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors: Chad R
authors: CR
authors: Frasier
authors: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109.
authors: Jacy L
authors: JL
authors: Wagnon
authors: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors: Yangyang Oliver
authors: YO
authors: Bao
authors: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors: Luke G
authors: LG
authors: McVeigh
authors: Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors: Luis F
authors: LF
authors: Lopez-Santiago
authors: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109.|Department of Neurology, University of Michigan, Ann Arbor, MI 48109.
authors: Miriam H
authors: MH
authors: Meisler
authors: 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: Lori L
authors: http://orcid.org/0000-0002-9479-6729
authors: LL
authors: Isom
keywords: arrhythmia; channelopathy; epilepsy; mutation; sodium channel