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 8

Spike-induced increase of [K+]out is directly involved in CSD induction by spatial illumination.

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Spike-induced increase of [K+]out is directly involved in CSD induction ...
(A) Experimental setting for spatial 470 nm illumination used to specifically control the area of CSD induction, allowing [K+]out, LFP, and IOS recordings at the site of CSD initiation. See Supplemental Videos 6 and 7. (B) [K+]out dynamics before and during CSD, correlated to the LFP and MUAs, which were paroxysmal at CSD initiation. Only the first component of the CSD is shown. (C) Enlargement and superposition of [K+]out and MUA traces shown in B. (D) Quantifications of [K+]out after the first 5 seconds of illumination, at the beginning of the paroxysmal MUA firing and at the end of the MUA firing (beginning of the depolarizing block) (arrows in B and C), n = 9 slices. Bars represent medians. Friedman test (P < 0.0001) and Dunn’s post hoc test (***P < 0.001). (E) Success rate of CSD induced by long-lasting puff of 12 mM KCl (dissolved in 125 mM NaCl), which corresponds to the [K+]out at the beginning of the depolarizing block, compared with a control 137 mM NaCl solution (Ctrl; Fisher’s exact test, **P = 0.0027). Injection area: 0.75 ± 0.11 mm2 (n = 10 slices with successful CSD inductions). See Supplemental Video 8. (F) Representative simultaneous juxtacellular–loose patch recordings of a GABAergic interneuron (upper trace) and of a pyramidal neuron (bottom trace) at the site of initiation of CSD induced with spatial optogenetic illumination as in A (see Supplemental Video 9); the negative deflection is the LFP generated by the CSD and recorded by the juxtacellular electrode. Scale bars: 500 μV, 5 seconds. The right traces show the firing (1.5 Hz high pass filtered to remove the slow components) immediately before the CSD initiation (highlighted in the traces on the left with the dashed boxes). See text for n and statistics.