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
View: Text | PDF
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

×

Figure 7

Effect of block of KCC2, neuronal excitability, or synaptic transmission on optogenetic CSD induction.

Options: View larger image (or click on image) Download as PowerPoint
Effect of block of KCC2, neuronal excitability, or synaptic transmission...
(A) Success rate of optogenetic CSD in VGAT-ChR2 slices in control (100%, n = 39) with the KCC2 blocker VU0240551 10 μM (100%, n = 12), the KCC2 blocker VU04663271 10 μM (85%, n = 20), the GABA-A agonist Isoguvacine 10 μM (100%, n = 11), or VU0463271 10 μM + Isoguvacine 10 μM (90%, n = 10); P = 0.0493 overall Fisher’s exact test, not significant with Bonferroni-corrected pairwise test. (B) Latency to optogenetic CSD induction in VGAT-ChR2 slices in control (median = 14.0 seconds, mean ± SEM = 20.0 ± 2.3 seconds; n = 38), with VU0240551 (14.0, 21.0 ± 4.2 seconds, n = 12), with VU04663271 (13.0, 16.5 ± 3.5 seconds, n = 11), Isoguvacine (15.0, 19.0 ± 3.5 seconds, n = 11), or VU0463271 + Isoguvacine (12, 24 ± 9.1 seconds, n = 9) (Kruskal-Wallis test, P = 0.93). (C) CSD propagation speed in control (median = 3.42 mm/min, mean ± SEM = 3.38 ± 0.13 seconds; n = 38), with VU0240551 (2.89, 3.12 ± 0.26 mm/min, n = 12), with VU04663271 (3.28, 3.32 ± 0.18 mm/min, n = 15), Isoguvacine (3.12, 3.08 ± 0.25 mm/min, n = 11), or VU0463271 + Isoguvacine (3.00, 3.19 ± 0.16 mm/min, n = 9) (Kruskal-Wallis test, P = 0.93). (D) Success rate of optogenetic CSD in VGAT-ChR2 slices in control (100%, n = 39) with the Na+ channel blocker TTX 1 μM (0%; n = 13), with GABA-A (Gabazine 15 μM) and/or NMDA-AMPA-Kainate (CPP 10 μM, CNQX 20 μM) receptor antagonists (Gabazine 0%, n = 6; CCP+CNQX, 100%, n = 16; Gabazine+CCP+CNQX, 90%, n = 10), or the Ca2+ channel blocker Cd2+ (100 μM) to fully block synaptic release (100%, n = 10) (Fisher’s exact test, ****P = 4 × 10–14; Bonferroni-corrected posttest, ****P < 0.0001 for TTX). (E) Latency to optogenetic CSD induction in control (median = 14.0 seconds, mean ± SEM = 17.6 ± 2.5 seconds; n = 29), with Gabazine (10.0, 11.2 ± 3.0 seconds, n = 6), with CPP+CNQX (23.0, 25.8 ± 3.4 seconds, n = 16), CPP+CNQX+Gabazine (20.0, 26.6 ± 9.1 seconds, n = 9) or Cd2+ (36.6, 38.3 ± 7.6 seconds, n = 10) (Kruskal-Wallis test, ***P = 0.0098; Dunn’s post hoc test, *P < 0.05 for Cd2+). (F) CSD propagation speed in control (median = 3.45 mm/min, mean ± SEM = 3.57 ± 0.18 seconds; n = 30), with Gabazine (5.28, 5.08 ± 0.44 mm/min, n = 6), with CPP+CNQX (1.39, 1.51 ± 0.11 mm/min, n = 16), CPP+CNQX +Gabazine (2.66, 2.97 ± 0.21 mm/min, n = 9), or Cd2+ (0.9, 1.03 ± 0.13 mm/min, n = 10) (Kruskal-Wallis test, ****P < 0.0001; Dunn’s post hoc test, *P = 0.011 for CPP+CNQX and ****P < 0.0001 for Cd2+).