Experimentally, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of NaV1.1 (SCN1A) cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking NaV1.1 gain-of-function to CSD generation in FHM3.
Those findings are supported by the two-neuron conductance-based model with dynamic ion concentrations we developed.
Chever O, Zerimech S, Scalmani P, Lemaire L, Pizzamiglio L, Loucif A, Ayrault M, Krupa M, Desroches M, Duprat F, Léna I, Cestèle S, Mantegazza M (2021) Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels J Clin Invest. [PubMed]