Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels
Oana Chever, … , Sandrine Cestèle, Massimo Mantegazza
Oana Chever, … , Sandrine Cestèle, Massimo Mantegazza
Published September 7, 2021
Citation Information: J Clin Invest. 2021;131(21):e142203. https://doi.org/10.1172/JCI142203.
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Research Article Neuroscience

Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels

Abstract

Spreading depolarizations (SDs) are involved in migraine, epilepsy, stroke, traumatic brain injury, and subarachnoid hemorrhage. However, the cellular origin and specific differential mechanisms are not clear. Increased glutamatergic activity is thought to be the key factor for generating cortical spreading depression (CSD), a pathological mechanism of migraine. Here, 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. Thus, we reveal the key role of hyperactivity of GABAergic interneurons in a mechanism of CSD initiation, which is relevant as a pathological mechanism of Nav1.1 FHM3 mutations, and possibly also for other types of migraine and diseases in which SDs are involved.

Authors

Oana Chever, Sarah Zerimech, Paolo Scalmani, Louisiane Lemaire, Lara Pizzamiglio, Alexandre Loucif, Marion Ayrault, Martin Krupa, Mathieu Desroches, Fabrice Duprat, Isabelle Léna, Sandrine Cestèle, Massimo Mantegazza

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Figure 3

CSD is triggered specifically in the neocortex by optogenetic-induced hyperactivity of GABAergic neurons.

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CSD is triggered specifically in the neocortex by optogenetic-induced hy...
(A) Experimental setting for optogenetic stimulations of a complete hemisphere in coronal slices (the area of illumination was larger than the area of image acquisition). (B) Representative CSD that was induced only in the neocortex in slices from VGAT-ChR2 mice containing neocortex, hippocampus, dorsal striatum, and thalamus, revealed by both the negative DC shift in the LFP and the IOS propagating wave. The 4 bottom panels are a time series corresponding to image-processed IOS acquisitions (one image every 5 seconds, the first one 5 seconds after CSD initiation; see Methods). Scale bars: 500 μm. (C) Distribution of latencies of CSD initiation upon 470 nm illumination in VGAT-ChR2 slices (median = 19 seconds, n = 103 slices) and distribution of propagation speed of optogenetic-induced CSD in VGAT-ChR2 slices (median = 3.18 mm/min, n = 103 slices). (D) Success rate of optogenetic CSD obtained in a different series of experiments comparing slices from VGAT-ChR2 (11/13 slices), WT (0/14), VGAT.Cre (0/10), and ChR2.lox (0/10) mice (Fisher’s exact test, ****P = 7 10–5). (E) Success rate of optogenetic CSD obtained in slices from PV-ChR2 mice (4/14 slices) or control PV-cre littermates (0/15 slices) (Fisher’s exact test, *P = 0.04). (F) Representative whole-cell patch-clamp recordings of GABAergic and pyramidal neurons in layer II–III upon optogenetic illumination: a fast-spiking GABAergic neuron responded to the 470 nm illumination (blue bar) with short latency, whereas a pyramidal neuron responded with longer latency. Scale bar: 20 seconds. (G) Overall latencies to spiking during 470 nm illumination for fast-spiking neurons (median = 0.30 seconds; n = 5) and pyramidal neurons (median = 22.26 seconds; n = 12) (Mann-Whitney test, ***P = 0.001). These recordings were not performed at the site of initiation, which, for this experimental setting, was variable within the neocortex and not identifiable a priori.