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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression
Author(s) -
EikermannHaerter Katharina,
Yuzawa Izumi,
Dilekoz Ergin,
Joutel Anne,
Moskowitz Michael A.,
Ayata Cenk
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22281
Subject(s) - cadasil , leukoencephalopathy , cortical spreading depression , familial hemiplegic migraine , migraine with aura , pathogenesis , migraine , pathology , mutation , biology , neuroscience , notch signaling pathway , aura , medicine , genetics , gene , disease
Migraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by NOTCH3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura. Ann Neurol 2011