Role of different voltage-gated Ca2+ channels in cortical spreading depression: Specific requirement of P/Q-type Ca2+ channels

Angelita Tottene, Andrea Urbani, Daniela Pietrobon

Research output: Contribution to journalArticlepeer-review

Abstract

Gain-of-function mutations in CaV2.1 (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 Ca2+ 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.1 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.

Original languageEnglish
JournalChannels
Volume5
Issue number2
Publication statusPublished - Mar 2011

Keywords

  • Calcium channel
  • Cortex
  • Migraine
  • NMDA receptor
  • Spreading depression
  • Synaptic transmission

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics

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