Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine.
Migraine is a very common disabling brain disorder with unclear pathogenesis. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in CaV2.1 (P/Q-type) Ca2+ channels. This review describes the functional consequences of FHM1 mutations in knockin mouse models carrying the mild R192Q or severe S218L mutations in the orthologous gene. The FHM1 knockin mice show allele dosage-dependent gain-of-function of neuronal P/Q-type Ca2+ current, reflecting activation of mutant channels at lower voltages, and allele dosage- and sex-dependent facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura. Gain-of-function of neuronal Ca2+ current, facilitation of CSD and post-CSD motor deficits were larger in S218L than R192Q knockin mice, in correlation with the more severe human S218L phenotype. Enhanced cortical excitatory neurotransmission, due to increased action potential-evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses, were demonstrated in R192Q knockin mice. Evidence for a causative link between enhanced glutamate release and CSD facilitation was obtained. The data from FHM1 mice strengthen the view of CSD as a key player in the pathogenesis of migraine, give insight into CSD mechanisms and point to episodic disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for vulnerability to CSD ignition in migraine.
Pietrobon
Daniela
D
Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy. daniela.pietrobon@unipd.it
D000818:Animals; D020864:Calcium Channels, N-Type / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000235:genetics* / Q000503:physiopathology*
D020864:Calcium Channels, N-Type