PuSH - Publication Server of Helmholtz Zentrum München: Hyperexcitable interneurons trigger cortical spreading depression in an <em>Scn1a</em> migraine model.

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... Journal

... Publication Type

... Research Data

... Publication Year

Publication overview

Support & Contact

Contact persons

Help

Data protection

Auffenberg, E.* ; Hedrich, U.B.S.* ; Barbieri, R.* ; Miely, D.* ; Groschup, B.* ; Wuttke, T.V.* ; Vogel, N.* ; Lührs, P.* ; Zanardi, I.* ; Bertelli, S.* ; Spielmann, N. ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Pusch, M.C.* ; Dichgans, M.* ; Lerche, H.* ; Gavazzo, P.* ; Plesnila, N.* ; Freilinger, T.*

Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model.

J. Clin. Invest. 131:e142202 (2021)

Publ. Version/Full Text

Postprint

DOI

PMC

	Open Access Gold (Paid Option)

Abstract
Metrics
Extra information

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q knock-in mice compared to wildtype mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation and increased ramp Na+-currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+-currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD.

Altmetric

Additional Metrics?

[➜Log in]

Edit extra informations Login

Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Monogenic Diseases ; Neurological Disorders ; Neuroscience ; Sodium Channels; Familial Hemiplegic Migraine; Severe Myoclonic Epilepsy; Action-potential Initiation; Reduced Sodium Current; Mouse Model; Inhibitory Interneurons; Gabaergic Interneurons; Sudden-death; Gene Scn1a; Channel

ISSN (print) / ISBN 0021-9738

e-ISSN 1558-8238

Journal Journal of Clinical Investigation

Quellenangaben Volume: 131, Issue: 21, Article Number: e142202

Publisher American Society of Clinical Investigation

Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)

Grants German Federal Ministry of Education and Research (BMBF project TREAT-Ion)
Faculty of Medicine, University of Tubingen intramural fortune grant
Vascular Dementia Research Foundation
Italian Telethon Foundation
Faculty of Medicine, University of Tubingen
International School for Advanced Studies (SISSA)
DFG
German Research Foundation (DFG)