A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.

Abstract	Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.
Authors	Arn M J M van den Maagdenberg, Daniela Pietrobon, Tommaso Pizzorusso, Simon Kaja, Ludo A M Broos, Tiziana Cesetti, Rob C G van de Ven, Angelita Tottene, Jos van der Kaa, Jaap J Plomp, Rune R Frants, Michel D Ferrari
Journal	Neuron (Neuron) Vol. 41 Issue 5 Pg. 701-10 (Mar 04 2004) ISSN: 0896-6273 [Print] United States
PMID	15003170 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	CACNA1A protein, human Calcium Channels Calcium Channels, N-Type Calcium Channels, P-Type Calcium Channels, Q-Type voltage-dependent calcium channel (P-Q type)
Topics	Animals Calcium Channels (biosynthesis, genetics) Calcium Channels, N-Type Calcium Channels, P-Type Calcium Channels, Q-Type Cells, Cultured Cortical Spreading Depression (genetics) Disease Models, Animal Female Genetic Predisposition to Disease Humans Male Mice Mice, Mutant Strains Mice, Transgenic Migraine with Aura (genetics, metabolism) Motor Endplate (genetics, metabolism) Mutation Recombination, Genetic

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