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GABAergic neurons and Na V 1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression

Abstract : 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 Na V 1.1 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 Na V 1.1 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 Na V 1.1 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 Na v 1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which is relevant for FHM3 and possibly also for other types of migraine.
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Preprints, Working Papers, ...
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https://hal.inria.fr/hal-03045625
Contributor : Mathieu Desroches <>
Submitted on : Tuesday, December 8, 2020 - 9:58:51 AM
Last modification on : Friday, January 22, 2021 - 10:48:03 AM

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Oana Chever, Sarah Zerimech, Paolo Scalmani, Louisiane Lemaire, Alexandre Loucif, et al.. GABAergic neurons and Na V 1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression. 2020. ⟨hal-03045625⟩

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