Waves of cerebral cortex depolarization: focus on a novel mechanism of migraine-linked cortical spreading depression induced by hyperactivation of GABAergic neurons.

Massimo Mantegazza
Université Côte d'Azur, CNRS UMR7275 IPMC, 660 Route des Lucioles, 06560 Valbonne, FranceIPMC

Spreading depolarization (SD) refers to waves of abrupt, sustained mass depolarization in the gray matter of the central nervous system, observed in different pathological conditions. Cortical spreading depression (CSD) is a SD generated in well-nourished and oxygenated tissue, and characterized by transient intense neuronal firing leading to a long lasting depolarizing block of neuronal activity. CSD is a proposed pathological mechanism of migraine. Some molecular/cellular mechanisms of migraine with aura and of CSD have been identified studying a rare genetic form: familial hemiplegic migraine (FHM). FHM type 3 is caused by mutations of the SCN1A gene, leading to gain of function of NaV1.1 sodium channels, which are essential for GABAergic neurons’ excitability. I will present our recent results about mechanisms of induction of CSD caused by gain of function of Nav1.1. Acute activation of Nav1.1 with a selective toxin in brain slices, mimicking the effect of FHM3 mutations, induce SD selectively in the cerebral cortex. We tested the role of GABAergic neurons by activating them with optogenetic techniques. Hyperactivity of interneurons is sufficient to ignite CSD by spiking-induced extracellular K+ build-up in the cerebral cortex, but not in other brain structures. GABAergic and glutamatergic synaptic transmission was not required for CSD initiation, but glutamatergic transmission was implicated in CSD propagation in the cortex. These results reveal the key role of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which can be relevant for FHM3 and possibly also for other types of migraine.