First FHM3 mouse model shows spontaneous cortical spreading depolarizations

Abstract

Here we show, for the first time, spontaneous cortical spreading depolarization (CSD) eventsthe electrophysiological correlate of the migraine aurain animals by using the first generated familial hemiplegic migraine type 3 (FHM3) transgenic mouse model. The mutant mice express L263V-mutated a1 subunits in voltage-gated Na V 1.1 sodium channels (Scn1a L263V ). CSDs consistently propagated from visual to motor cortex, recapitulating what has been shown in patients with migraine with aura. This model may be valuable for the preclinical study of migraine with aura and other diseases in which spreading depolarization is a prominent feature.

GABAergic neurons and NaV1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression

“…Interestingly, a recent work shows that knock-in mice carrying the FHM3 L263V NaV1.1 mutation experience spontaneous CSD events but not seizures, although detailed mechanisms of CSD generation have not been studied (Jansen et al, 2019). Thus, these results point to different, novel and counterintuitive mechanisms in comparison to FHM1 and FHM2 mutations.…”

Diagnostic and therapeutic aspects of hemiplegic migraine

“…43 The increase of extracellular potassium concentration consequent to the increased firing of GABAergic interneurons has been proposed as a possible mechanism underlying increased propensity to CSD in FHM3. 44 Searching for other potential HM genes, PRRT2 has been suggested as the fourth HM gene. 45 46 It encodes a presynaptic transmembrane protein which is involved in synaptic vesicles fusion and regulation of voltage-gated calcium channel in glutamatergic neurons.…”

“… 43 The increase of extracellular potassium concentration consequent to the increased firing of GABAergic interneurons has been proposed as a possible mechanism underlying increased propensity to CSD in FHM3. 44 …”

Non-canonical glutamate signaling in a genetic model of migraine with aura

“…In addition to being responsible for the aura, SD initiates headache mechanisms in animal models (Burstein et al, 2015;Pietrobon and Moskowitz, 2014), and is thus the earliest physiologically measurable feature of the migraine attack. Monogenic forms of migraine have been used to generate mouse models, and despite mechanistically diverse mutations, thus far all models show an increased susceptibility to SD (Brennan et al, 2013;Capuani et al, 2016;Jansen et al, 2019;Leo et al, 2011;van den Maagdenberg et al, 2004;Tottene et al, 2009). Familial hemiplegic migraine, type 2 (FHM2) is a form of migraine with aura that arises from loss of function mutations to ATP1A2, the gene encoding the predominantly astrocytic α 2 Na + /K + -ATPase (α2NKA) (De Fusco et al, 2003;Gritz and Radcliffe, 2013;Pietrobon, 2007).…”