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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)
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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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 131, Heft: 21, Seiten: , Artikelnummer: e142202 Supplement: ,
Verlag American Society of Clinical Investigation
Verlagsort 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500600-001
G-500692-001
Förderungen 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)
DOI 10.1172/JCI142202
WOS ID WOS:000715014400004
Scopus ID 85118489577
PubMed ID 34546973
Erfassungsdatum 2021-09-24
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