Enhanced Subcortical Spreading Depression in Familial Hemiplegic Migraine Type 1 Mutant Mice

Abstract

Familial hemiplegic migraine type 1, a monogenic migraine variant with aura, is linked to gain-of-function mutations in the CACNA1A gene encoding CaV2.1 channels. The S218L mutation causes severe channel dysfunction, and paroxysmal migraine attacks can be accompanied by seizures, coma, and hemiplegia; patients expressing the R192Q mutation exhibit hemiplegia only. Familial hemiplegic migraine knock-in mice expressing the S218L or R192Q mutation are highly susceptible to cortical spreading depression, the electrophysiological surrogate for migraine aura, and develop severe and prolonged motor deficits after spreading depression. The S218L mutants also develop coma and seizures and sometimes die. To investigate underlying mechanisms for these symptoms, we used multielectrode electrophysiological recordings, diffusion-weighted magnetic resonance imaging, and c-fos immunohistochemistry to trace spreading depression propagation into subcortical structures. We showed that unlike the wild type, cortical spreading depression readily propagated into subcortical structures in both familial hemiplegic migraine type 1 mutants. Whereas the facilitated subcortical spread appeared limited to the striatum in R192Q, hippocampal and thalamic spread was detected in the S218L mutants with an allele-dosage effect. Both strains exhibited increased susceptibility to subcortical spreading depression and reverberating spreading depression waves. Altogether, these data show that spreading depression propagates between cortex, basal ganglia, diencephalon, and hippocampus in genetically susceptible brains, which could explain the prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura.

In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures

“…A previous report found that SD is constrained to the cortex in WT mice but can invade the striatum in R192Q mice and can invade the striatum, hippocampus, and, occasionally, thalamus in S218L mice (28). Our data generally are in line with these findings, except that we did not observe SD invasion of the thalamus in S218L animals (Figs.…”

“…Because WT animals did not display subcortical SD in vivo, it is likely that, like the hippocampus, the striatum is capable of SD but cannot normally propagate the wave in response to adjacent cortical SD. It has been suggested that in FHM-1 mice SD may spread to the striatum and hippocampus via the amygdala and subiculum, respectively, and that lower neuronal densities in these areas may be responsible for limiting SD spread in WT animals (28). Our data from R192Q animals support this view with respect to the anatomical entry point of SD into these structures for this strain.…”

“…In S218L mice, in which SD spreads immediately from the adjacent cortex to subcortical structures, the stronger gain-of-function effect of the mutation on Ca V 2.1 channels apparently generates an SD wave that is sufficiently powerful to traverse the corpus callosum. Of further interest is that SD is not observed to propagate into the thalamus for either of the FHM-1 mutations, although this propagation has been reported to occur in a percentage of S218L mice (28). It should be considered that in the study by EikermannHaerter et al (28) the electrophysiological measurements of SD were made under pentobarbital anesthesia, whereas our experiments were performed under isoflurane anesthesia; the two anesthetics may have distinct effects on SD invasion into the thalamus (35).…”

“…Of further interest is that SD is not observed to propagate into the thalamus for either of the FHM-1 mutations, although this propagation has been reported to occur in a percentage of S218L mice (28). It should be considered that in the study by EikermannHaerter et al (28) the electrophysiological measurements of SD were made under pentobarbital anesthesia, whereas our experiments were performed under isoflurane anesthesia; the two anesthetics may have distinct effects on SD invasion into the thalamus (35). Despite this difference, both studies indicate that the white matter of the internal capsule appears to be a particularly difficult region for SD to traverse.…”

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

“…SD and calcium homeostasis have been extensively studied in voltage-gated P/Q-type Ca 2+ channel mutations, where a gain-of-function results in a several-fold decrease in cortical SD threshold. The degree of facilitation of the SD phenotype in RQ mutants detected here is somewhat smaller than that found in one of the PQ channel mutants, R192Q, where SD propagation was greatly enhanced and SD propagated into subcortical structures (38). These mutant mice also had spontaneous seizures and shorter survival than the RQ mutant mice studied here.…”