TY - JOUR
T1 - Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice
AU - Eikermann-Haerter, Katharina
AU - Yuzawa, Izumi
AU - Qin, Tao
AU - Wang, Yumei
AU - Baek, Kwangyeol
AU - Kim, Young Ro
AU - Hoffmann, Ulrike
AU - Dilekoz, Ergin
AU - Waeber, Christian
AU - Ferrari, Michel D.
AU - van den Maagdenberg, Arn M.J.M.
AU - Moskowitz, Michael A.
AU - Ayata, Cenk
PY - 2011/4/13
Y1 - 2011/4/13
N2 - 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 beaccom-panied by seizures, coma, and hemiplegia; patients expressing the R192Qmutation exhibit hemiplegiaonly. Familia lhemiplegic 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 in to subcortical structures in both familial hemiplegic migraine type 1 mutants. Whereas the facilitated subcortical spread ap-pearedlimitedtothestriatuminR192Q, hippocampalandthalamicspread was detected in the S218L mutantswithanallele-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.
AB - 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 beaccom-panied by seizures, coma, and hemiplegia; patients expressing the R192Qmutation exhibit hemiplegiaonly. Familia lhemiplegic 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 in to subcortical structures in both familial hemiplegic migraine type 1 mutants. Whereas the facilitated subcortical spread ap-pearedlimitedtothestriatuminR192Q, hippocampalandthalamicspread was detected in the S218L mutantswithanallele-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.
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U2 - 10.1523/JNEUROSCI.5346-10.2011
DO - 10.1523/JNEUROSCI.5346-10.2011
M3 - Article
C2 - 21490217
AN - SCOPUS:79955765856
SN - 0270-6474
VL - 31
SP - 5755
EP - 5763
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 15
ER -