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.
Reference:
1 .
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]
|
