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Auffenberg, Eva; Hedrich, Ulrike B. S.; Barbieri, Raffaella; Miely, Daniela; Groschup, Bernhard; Wuttke, Thomas V.; Vogel, Niklas; Luehrs, Philipp; Zanardi, Ilaria; Bertelli, Sara; Spielmann, Nadine; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabe de Angelis, Martin; Pusch, Michael; Dichgans, Martin ORCID logoORCID: https://orcid.org/0000-0002-0654-387X; Lerche, Holger; Gavazzo, Paola; Plesnila, Nikolaus and Freilinger, Tobias (2021): Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model. In: Journal of Clinical Investigation, Vol. 131, No. 21, e142202 [PDF, 3MB]

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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 Na(V)1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1a(L1649Q) knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1a(L1649Q) 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 Scn1a(L1649Q) 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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