Neuronal calcium channels and migraine

Abstract

Migraine is a common disabling brain disorder of unknown etiology. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in CaV2.1 (P/Q-type) Ca2+ channels. CaV2.1 channels play a key role in initiating action potential-evoked neurotransmitter release at central synapses. FHM1 mutations shift channel activation to lower voltages and increase Ca2+ influx through single recombinant human CaV2.1 channels. Knockin mice carrying a human FHM1 mutation show an increased P/Q-type Ca2+ current in cerebellar and cortical neurons and a reduced threshold for and increased velocity of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. To investigate the mechanisms of CSD facilitation, we studied neurotransmission at synapses of cortical pyramidal cells in microculture and in connected pairs of layer 2/3 pyramidal cells and fast-spiking interneurons in acute thalamocortical slices. Our data show increased strength of excitatory neurotransmission due to enhanced action potential-evoked Ca2+ influx through synaptic CaV2.1 channels and increased probability of glutamate release at pyramidal cell synapses of FHM1 KI mice. At the same synapses, short-term depression during trains of action potentials was enhanced. There was no evidence of homeostatic compensatory mechanisms at synapses onto pyramidal cells. To investigate possible alterations of the cortical excitation-inhibition balance in FHM1, we studied inhibitory neurotransmission between fast-spiking interneurons and pyramidal cells in thalamocortical slices. At this inhibitory synapse the strength of neurotransmission was unaltered in KI mice. Our findings may explain CDS facilitation in FHM1 mice, and point to tipping the finely tuned dynamic balance between excitation and inhibition during cortical activity towards excitation as the basis for CSD propensity and abnormal processing of sensory information in migraine.