2. Academic Validation
  3. Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model

Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model

  • J Clin Invest. 2021 Nov 1;131(21):e142202. doi: 10.1172/JCI142202.
Eva Auffenberg 1 2,  Ulrike Bs Hedrich 1,  Raffaella Barbieri 3,  Daniela Miely 1,  Bernhard Groschup 2,  Thomas V Wuttke 1 4,  Niklas Vogel 1,  Philipp Lührs 1,  Ilaria Zanardi 3,  Sara Bertelli 3,  Nadine Spielmann 5,  Valerie Gailus-Durner 5,  Helmut Fuchs 5,  Martin Hrabě de Angelis 5 6 7,  Michael Pusch 3,  Martin Dichgans 2 8,  Holger Lerche 1,  Paola Gavazzo 3,  Nikolaus Plesnila 2 8,  Tobias Freilinger 1 9
Affiliations

Affiliations

  • 1 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 2 Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
  • 3 Biophysics Institute, Consiglio Nazionale delle Ricerche (CNR), Genoa, Italy.
  • 4 Department of Neurosurgery, University of Tübingen, Tübingen, Germany.
  • 5 German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • 6 Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany.
  • 7 German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • 8 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 9 Department of Neurology, Klinikum Passau, Passau, Germany.
PMID: 34546973 DOI: 10.1172/JCI142202
Abstract

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 with WT 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.

Keywords

Monogenic diseases; Neurological disorders; Neuroscience; Sodium channels.

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