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

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

doi:10.1172/jci142203

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.

Highlights

Spreading depolarizations (SDs) are waves of transient intense hyperexcitability of brain networks, which initiate focally and slowly propagate, accompanied by modifications of ionic gradients and cell swelling [1, 2]
We and others have provided evidence that, in contrast to epileptogenic mutations, familial hemiplegic migraine type-3 (FHM3) mutations cause gain of function of the channel, often increasing persistent current and inducing hyperexcitability of transfected GABAergic neurons in primary culture [21,22,23,24,25,26,27,28,29,30], which could be responsible for cortical spreading depression (CSD) initiation, as we have recently proposed in a computational model [31, 32]
We identified and characterized a mechanism of CSD initiation specific of the neocortex, showing in acute experimental models a causal relationship between NaV1.1 gain of function leading to initial hyperactivity of GABAergic neurons, progressive engagement of the whole neuronal network, and CSD ignition, driven by the progressive increase of [K+]out at the initiation site and in which synaptic transmission is not necessary

Summary

Introduction

Spreading depolarizations (SDs) are waves of transient intense hyperexcitability of brain networks, which initiate focally and slowly propagate, accompanied by modifications of ionic gradients and cell swelling [1, 2]. SDs generated in normoxic conditions are implicated in migraine and epilepsy. SDs generated in anoxic/hypoxic conditions are implicated in stroke, traumatic brain injury, and subarachnoid hemorrhage [1, 2, 8]. SDs have been observed and extensively studied for decades, but specific pathological mechanisms that lead to their initiation and propagation are not clear, it is hypothesized that glutamatergic activity plays a key role, in particular in CSD [1, 2]

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Results

Conclusion