A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.
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.
Pubmed ID: 15003170 RIS Download
Animals | Calcium Channels | Calcium Channels, N-Type | Calcium Channels, P-Type | Calcium Channels, Q-Type | Cells, Cultured | Cortical Spreading Depression | Disease Models, Animal | Female | Genetic Predisposition to Disease | Humans | Male | Mice | Mice, Mutant Strains | Mice, Transgenic | Migraine with Aura | Motor Endplate | Mutation | Recombination, Genetic