title: Role of different voltage-gated Ca2+ channels in cortical spreading depression: specific requirement of P/Q-type Ca2+ channels.
abstract: Gain-of-function mutations in CaV 2.1 (P/Q-type) Ca2+ channels cause familial hemiplegic migraine type 1 (FHM1), a subtype of migraine with aura. Knockin (KI) mice carrying FHM1 mutations show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. We recently studied cortical neurotransmission in neuronal microcultures and brain slices of FHM1 KI mice, and showed (1) gain-of-function of 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, and (2) a causative link between enhanced glutamate release and facilitation of CSD induced by brief pulses of high K+ in cortical slices. Here, we show that after blockade of either the P/Q-type Ca2+ channels or the NMDA receptors, CSD cannot be induced in wild-type mouse cortical slices. In contrast, blockade of N- or R-type Ca2+ channels has only a small inhibitory effect on CSD threshold and velocity of propagation. Our findings support a model in which Ca2+ influx through presynaptic P/Q-type Ca2+ channels with consequent release of glutamate from recurrent cortical pyramidal cell synapses and activation of NMDA receptors are required for initiation and propagation of the CSD involved in migraine.
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padua, Italy.
authors.forename: Angelita
authors.initials: A
authors.lastname: Tottene
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietrobon
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry*; D020865:Calcium Channels, P-Type / Q000378:metabolism*; D020907:Calcium Channels, Q-Type / Q000378:metabolism*; D002478:Cells, Cultured; D013181:Cortical Spreading Depression; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D015220:Calcium Channels; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D002118:Calcium