Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model.
J Clin Invest. 2021 Sep 21:e142202. doi: 10.1172/JCI142202. Epub ahead of print. PMID: 34546973.
| Authors/Editors: | Auffenberg E, Hedrich UB, Barbieri R, Miely D, Groschup B, Wuttke TV, Vogel N, Lührs P, Zanardi I, Bertelli S, Spielmann N, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Pusch M, Dichgans M, Lerche H, Gavazzo P, Plesnila N, Freilinger T. |
|---|---|
| Publication Date: | 2021 |
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 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.
Keywords: Monogenic diseases; Neurological disorders; Neuroscience; Sodium channels.
