GABAergic neurons and Na_V1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression

Abstract

Cortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel neocortex-specific mechanism of CSD initiation and a novel pathological role of GABAergic neurons.Mutations of the NaV1.1 sodium channel (the SCN1A gene), which is particularly important for GABAergic neurons' excitability, cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura. They induce gain-of-function of NaV1.1 and hyperexcitability of GABAergic interneurons in culture. However, the mechanism linking these dysfunctions to CSD and FHM3 has not been elucidated. Here, we show that NaV1.1 gain-of-function, induced by the specific activator Hm1a, or mimicked by optogenetic-induced hyperactivity of cortical GABAergic neurons, is sufficient to ignite CSD by spiking-generated extracellular K + build-up. This mechanism is neocortex specific because, with these approaches, CSD was not generated in other brain areas. GABAergic and glutamatergic synaptic transmission is not required for optogenetic CSD initiation, but glutamatergic transmission is implicated in CSD propagation. Thus, our results reveal the key role of hyper-activation of Nav1.1 and GABAergic neurons in a novel mechanism of CSD initiation, which is relevant for FHM3 and possibly also for other types of migraine.

Modeling NaV1.1/SCN1A sodium channel mutations in a microcircuit with realistic ion concentration dynamics suggests differential GABAergic mechanisms leading to hyperexcitability in epilepsy and hemiplegic migraine

“…We present original experimental results that support predictions of the model and we put the model simulations into perspective with other experimental works. In particular, we qualitatively compared them with results we obtained using the Hm1a Na V 1.1 enhancer to mimic FHM-3 mutations [29] and with results of Freilinger et al (personal communication; see acknowledgments), who generated the knock-in mouse model of the L1649Q FHM-3 mutation studying effects on microcircuit features.…”

“…model of fast-spiking cortical interneurons by Golomb et al [33], which is presented in Section 2.2.5. Indeed, CSD that causes migraine aura is generated in the neocortex and experimental results suggest the FHM-3 CSD is selectively initiated in the neocortex [29].…”

“…12567) [49] with hemizygous Viaat-Cre transgenic males, in which selective Cre recombinase expression in GABAergic neurons is driven by the vesicular GABA transporter (VGAT) promoter (B6.FVB-Tg(Slc32a1-Cre)2.1Hzo/FrkJ; JAX n˚017535), line 2.1 in [50]). Offspring was genotyped by PCR, following the standard JAX protocols for VGAT-ChR2 mice and using our standard protocol for Scn1a +/mice [29,47], or selecting fluorescent pups monitored with a Dual Fluorescent Protein flashlight (NightSea).…”

Kcnq2/Kv7.2 controls the threshold and bihemispheric symmetry of cortical spreading depolarization

“…CACNA1A 18,19 ), impaired extracellular K + clearance (FHM2: ATP1A2 20,21 ), and defective inhibitory neuron excitability (FHM 3: SCN1A 22,23 ). These genes assign an SD threshold-determining role to excitatory /inhibitory synaptic function and ionic homeostasis in the interstitial space.…”

“…Similarly, while fewer in number, genetic analysis of complicated migraine with aura syndromes such as familial hemiplegic migraine (FHM) reveal molecular mechanisms underlying SD threshold and susceptibility. The genes identified in FHM so far share a risk of developmental epileptic co-morbidity via distinct mechanisms, including calcium current facilitation of synaptic glutamate release (FHM1: CACNA1A 18,19 ), impaired extracellular K + clearance (FHM2: ATP1A2 20,21 ), and defective inhibitory neuron excitability (FHM 3: SCN1A 22,23 ). These genes assign an SD threshold-determining role to excitatory /inhibitory synaptic function and ionic homeostasis in the interstitial space.…”