title: Migraine pathophysiology: lessons from mouse models and human genetics.
abstract: Migraine is a common, disabling, and undertreated episodic brain disorder that is more common in women than in men. Unbiased genome-wide association studies have identified 13 migraine-associated variants pointing at genes that cluster in pathways for glutamatergic neurotransmission, synaptic function, pain sensing, metalloproteinases, and the vasculature. The individual pathogenetic contribution of each gene variant is difficult to assess because of small effect sizes and complex interactions. Six genes with large effect sizes were identified in patients with rare monogenic migraine syndromes, in which hemiplegic migraine and non-hemiplegic migraine with or without aura are part of a wider clinical spectrum. Transgenic mouse models with human monogenic-migraine-syndrome gene mutations showed migraine-like features, increased glutamatergic neurotransmission, cerebral hyperexcitability, and enhanced susceptibility to cortical spreading depression, which is the electrophysiological correlate of aura and a putative trigger for migraine. Enhanced susceptibility to cortical spreading depression increased sensitivity to focal cerebral ischaemia, and blocking of cortical spreading depression improved stroke outcome in these mice. Changes in female hormone levels in these mice modulated cortical spreading depression susceptibility in much the same way that hormonal fluctuations affect migraine activity in patients. These findings confirm the multifactorial basis of migraine and might allow new prophylactic options to be developed, not only for migraine but potentially also for migraine-comorbid disorders such as epilepsy, depression, and stroke.
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands. Electronic address: M.D.Ferrari@lumc.nl.
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Roselin R
authors.initials: RR
authors.lastname: Klever
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.affiliation: Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands; Department of Human Genetics, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008881:Migraine Disorders / Q000235:genetics* / Q000503:physiopathology*