TY - JOUR T1 - GABAergic neurons and Na<sub>V</sub>1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression JF - bioRxiv DO - 10.1101/2020.03.14.991158 SP - 2020.03.14.991158 AU - Oana Chever AU - Sarah Zerimech AU - Paolo Scalmani AU - Louisiane Lemaire AU - Alexandre Loucif AU - Marion Ayrault AU - Martin Krupa AU - Mathieu Desroches AU - Fabrice Duprat AU - Sandrine Cestèle AU - Massimo Mantegazza Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/03/14/2020.03.14.991158.abstract N2 - Cortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel neocortex-specific mechanism of CSD initiation and a novel pathological role of GABAergic neurons. Mutations of the NaV1.1 sodium channel (the SCN1A gene), which is particularly important for GABAergic neurons’ excitability, cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura. They induce gain-of-function of NaV1.1 and hyperexcitability of GABAergic interneurons in culture. However, the mechanism linking these dysfunctions to CSD and FHM3 has not been elucidated. Here, we show that NaV1.1 gain-of-function, induced by the specific activator Hm1a, or mimicked by optogenetic-induced hyperactivity of cortical GABAergic neurons, is sufficient to ignite CSD by spiking-generated extracellular K+ build-up. This mechanism is neocortex specific because, with these approaches, CSD was not generated in other brain areas. GABAergic and glutamatergic synaptic transmission is not required for optogenetic CSD initiation, but glutamatergic transmission is implicated in CSD propagation. Thus, our results reveal the key role of hyper-activation of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which is relevant for FHM3 and possibly also for other types of migraine. ER -