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 4

Effect of Hm1a on optogenetic CSD induction.

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Effect of Hm1a on optogenetic CSD induction. (A) Further series of exper...
(A) Further series of experiments in which features of optogenetic CSD induction were compared in VGAT-ChR2 slices perfused with Hm1a (but in which the toxin did not induce CSD within 10 minutes) and control VGAT-ChR2 slices, waiting 10 minutes to illuminate (these experiments are included in Figure 1D). (B) Latencies of optogenetic CSD measured in control VGAT-ChR2 slices (median = 24 seconds, mean ± SEM = 27.3 ± 3.4 seconds; n = 15 slices) and VGAT-ChR2 slices perfused with Hm1a (median = 14 seconds, mean ± SEM = 19.8 ± 3.4 seconds; n = 20 slices) (Mann-Whitney test, *P = 0.014). (C) Propagation speed of optogenetic CSD in the same slices (control VGAT-ChR2, median = 3.14 mm/min, mean ± SEM = 3.0 ± 0.1 mm/min, n = 15 slices; VGAT-ChR2 slices perfused with Hm1a without CSD, median = 3.50 mm/min, mean ± SEM = 3.6 ± 0.2 mm/min, n = 20 slices) (Mann-Whitney test, *P = 0.025). (D) Duration of optogenetic-induced CSD measured at half width of the LFP DC shift (control VGAT-ChR2 slices, median = 38.1 seconds, mean ± SEM = 41.1 ± 4.4 seconds, n = 15 slices, VGAT-ChR2 slices perfused with Hm1a but without CSD, median = 38.3 seconds, mean ± SEM = 38.7 ± 1.7 seconds, n = 6 slices) (Mann-Whitney test, P = 0.7).