Impaired Action Potential Initiation in GABAergic Interneurons Causes Hyperexcitable Networks in an Epileptic Mouse Model Carrying a Human Na(V)1.1 Mutation

• Type of Material: Article
• Authors: Ulrike B. S. Hedrich, University of Tübingen; Camille Liautard, CNRS UMR 7275; Daniel Kirschenbaum, University of Tübingen; Martin Pofahl, University of Bonn; Jennifer Lavigne, CNRS UMR 7275; Yuanyuan Liu, University of Tübingen; Stephan Theiss, Heinrich Heine University; Johannes Slotta, Heinrich Heine University; Andrew Escayg, Emory University; Marcel Dihne, University of Tübingen; Heinz Beck, University of Bonn Medical Center; Massimo Mantegazza, CNRS UMR 7275; Holger Lerche, University of Tübingen
• Language: English
• Date: 2014-11-05
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: © 2014 the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.0721-14.2014
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 34
• Issue: 45
• Start Page: 14874
• End Page: 14889
• Grant/Funding Information: This work was supported by the Deutsche Forschungsgemeinschaft (Grants Le1030/10-1/2 to H.L. and SFB 1089 to H.B.); the Bundesministerium für Bildung und Forschung (National Genome Research Network/Epilepsy and Migraine integrated network Grants 01GS08123 and 01GS08122 to H.L. and H.B.; EuroTransBio/ESSENCE Grant FKZ0315641A to M.D., S.T., and J.S.); the European Commission (Grant EPICURE, LSHM-CT-2006-037315 to H.L., M.M., and H.B.); Laboratory of Excellence Ion Channel Science and Therapeutics (to M.M.); and the Fondation Recherche Medicale (to M.M.).; Research for this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Grant R01-NS072221 (to A.E.).
• Keywords: Neurosciences & Neurology; SCN2A MUTATION; SCN1A; MECHANISMS; REVEALS; Neurosciences; genetics; network activity; HIPPOCAMPUS; epilepsy; GENERALIZED EPILEPSY; Science & Technology; Life Sciences & Biomedicine; ion channel; SEVERE MYOCLONIC EPILEPSY; SODIUM-CHANNEL; FEBRILE SEIZURES PLUS; NEURONS; mouse model
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the Nav1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na+channels in interneurons and persistent Na+currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca2+ imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.