title: Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations.
abstract: BACKGROUND
  Migraine is an independent risk factor for stroke. Mechanisms underlying this association are unclear. Familial hemiplegic migraine (FHM), a migraine subtype that also carries an increased stroke risk, is a useful model for common migraine phenotypes because of shared aura and headache features, trigger factors, and underlying glutamatergic mechanisms.
  
  
  RESULTS
  Here, we show that FHM type 1 (FHM1) mutations in Ca(V)2.1 voltage-gated Ca(2+) channels render the brain more vulnerable to ischemic stroke. Compared with wild-type mice, 2 FHM1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations associated with rapid expansion of infarct core on diffusion-weighted magnetic resonance imaging and larger perfusion deficits on laser speckle flowmetry. Cerebral blood flow required for tissue survival was higher in the mutants, leading to infarction with milder ischemia. As a result, mutants developed larger infarcts and worse neurological outcomes after stroke, which were selectively attenuated by a glutamate receptor antagonist.
  
  
  CONCLUSIONS
  We propose that enhanced susceptibility to ischemic depolarizations akin to spreading depression predisposes migraineurs to infarction during mild ischemic events, thereby increasing the stroke risk.
authors.affiliation: Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Izumi
authors.initials: I
authors.lastname: Yuzawa
authors.forename: Christina H
authors.initials: CH
authors.lastname: Liu
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Tao
authors.initials: T
authors.lastname: Qin
authors.forename: Tobias
authors.initials: T
authors.lastname: Kurth
authors.forename: Christian
authors.initials: C
authors.lastname: Waeber
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moskowitz
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D020864:Calcium Channels, N-Type / Q000235:genetics; D002560:Cerebrovascular Circulation; D013181:Cortical Spreading Depression; D004198:Disease Susceptibility; D008279:Magnetic Resonance Imaging; D051379:Mice; D008881:Migraine Disorders / Q000150:complications / Q000235:genetics*; D020325:Migraine with Aura / Q000235:genetics; D009154:Mutation; D020521:Stroke / Q000209:etiology* / Q000235:genetics
chemical_list: D020864:Calcium Channels, N-Type