Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels
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
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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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 9

CSD induction in vivo.

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CSD induction in vivo. (A) Experimental design of optogenetic induction:...
(A) Experimental design of optogenetic induction: blue light optogenetic stimulation (100 Hz trains of 0.8 ms pulses) was applied to the barrel cortex of anesthetized mice with an optical fiber through a craniotomy; DC field potential recordings were performed with a glass pipette (Ag/AgCl electrode). (B) Representative field potential traces of CSD in a VGAT-ChR2 mouse, whereas there was no response in a control WT mouse. (C) Proportion of optogenetic CSD induction in VGAT-ChR2 (5/10) and control mice (0/13, including WT, n = 5, VGAT.Cre, n = 4, and ChR2.lox, n = 4; Fisher’s exact test, **P = 0.0075). (D) Experimental design of Hm1a injections into the somatosensory cortex: CSD was induced by injecting 130 mM KCl with a 30-gauge needle and monitored by DC field potential recordings (1.3 mm more rostral), Hm1a or ACSF (negative control) were injected at the same location after CSD induction, and then a second CSD was induced by injecting again with 130 mM KCl. (E) Representative CSD traces obtained before (top) and after (bottom) the injection of 10 nM Hm1a. (F) Representative traces obtained before (top) and after (bottom) the injection of ACSF. (G) Comparison of CSD latency observed before and after injection of ACSF (control) or Hm1a 10 nM: 103 seconds (median), 121 ± 18 seconds (mean ± SEM) before ACSF; 129 seconds, 123 ± 8 seconds after ACSF (n = 6; Wilcoxon’s signed ranks test, P = 0.69); 100 seconds, 123 ± 23 seconds before Hm1a 10 nM; 90 seconds, 99 ± 16 seconds after Hm1a 10 nM (n = 8; Wilcoxon’s signed ranks test; *P = 0.016). Scale bars: 5 mV, 1 minute for all the panels.