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.
van den Maagdenberg
Arn M J M
AM
Department of Biomedical Sciences, University of Padova, CNR Institute of Neuroscience, Viale G. Colombo 3, 35121 Padova, Italy. dani@civ.bio.unipd.it
Pietrobon
Daniela
D
Pizzorusso
Tommaso
T
Kaja
Simon
S
Broos
Ludo A M
LA
Cesetti
Tiziana
T
van de Ven
Rob C G
RC
Tottene
Angelita
A
van der Kaa
Jos
J
Plomp
Jaap J
JJ
Frants
Rune R
RR
Ferrari
Michel D
MD
D000818:Animals; D015220:Calcium Channels / Q000096:biosynthesis / Q000235:genetics*; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002478:Cells, Cultured; D013181:Cortical Spreading Depression / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000235:genetics* / Q000378:metabolism; D009045:Motor Endplate / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011995:Recombination, Genetic
D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; C105656:CACNA1A protein, human