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 haemorrhage. However, the cellular origin and specific differential mechanisms are not clear yet. 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 Na V 1.1 (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 pathological mechanism of Nav1.1 FHM3 mutations, and possibly also for other types of migraine and diseases in which SDs are involved.

Functional Investigation of a Neuronal Microcircuit in the CA1 Area of the Hippocampus Reveals Synaptic Dysfunction in Dravet Syndrome Mice

“…Moreover, an examination of the threshold for AP demonstrated a more depolarized threshold voltage in DS ( Figure 1G ), in accordance with reduced firing of these SO interneurons. Next, we examined the effect of the application of Hm1a, at 50 nM, a concentration that was previously found to enhance the firing of fast spiking interneurons in DS mice ( Richards et al, 2018 ; Goff and Goldberg, 2019 ; Chever et al, 2021 ). The application of Hm1a had no significant effect on the firing rates of WT and DS ( Figures 1D,E ).…”

“…Another possible explanation for the lack of differences in the Hm1a impact on WT and DS SO interneurons, is that different Hm1a-sensitive sodium channel(s) repertoire is expressed in each genotype. Moreover, while Hm1a is relatively selective for Na V 1.1, at 50 nM there might be some modulation of additional Na V channels ( Osteen et al, 2016 ; Richards et al, 2018 ; Chever et al, 2021 ). One candidate is Na V 1.3, which also displays a relatively high affinity to Hm1a ( Osteen et al, 2016 ; Richards et al, 2018 ), and was suggested to be upregulated in DS mice ( Yu et al, 2006 ).…”

“…Interestingly, studies that utilized measurements of sodium currents in dissociated neurons or nucleated patches also reported similar sodium current densities in WT and DS neurons at this age group (at seizure onset) ( Hedrich et al, 2014 ; Rubinstein et al, 2015b ). Of note, other studies that examined the functional effect of Hm1a did not provide a direct comparison between the genotypes and reported on either DS ( Goff and Goldberg, 2019 ; Mattis et al, 2021 ) or WT ( Chever et al, 2021 ) interneurons.…”

Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

“…Although the pathophysiological phenotype for FHM1 and FHM2 converge on the glutamatergic synapse, this is not the case for SCN1A gene mutations underlying FHM3 (Desroches et al, 2019;Chever et al, 2021;Lemaire et al, 2021). SCN1A encodes the α1 subunit of the neuronal voltage-gated sodium channel Nav1.1, which contributes to the action potential firing on primarily GABAergic interneurons.…”

“…In FHM3, however, mutations are gain-of-function, causing increased firing of GABAergic interneurons. Increased GABAergic activity may sound at odds with CSD generation but recent studies have shed light on the mechanism of CSD initiation by documenting that hyperactive GABAergic interneurons discharging at high frequencies can cause significant elevations in extracellular K + (over 12 mM), hence, increase CSD susceptibility as discussed above ( Desroches et al, 2019 ; Chever et al, 2021 ; Lemaire et al, 2021 ). Supporting this view, knock-in mice bearing L263V or L1649Q human mutation exhibit a low CSD induction threshold ( Jansen et al, 2020 ; Auffenberg et al, 2021 ) as well as spontaneous CSDs ( Jansen et al, 2020 ) and hyperexcitable GABAergic neurons ( Auffenberg et al, 2021 ).…”