A rare subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by gain-of-function mutations in the gene that encodes the a₁ subunit of Ca_V2.1 (P/Q-type) Ca²⁺ channels. These neuronal Ca² channels play a dominant role in controlling neurotransmitter release at many cortical synapses. FHM1 knockin (KI) mice show increased P/Q Ca²⁺ current in cortical pyramidal cells and a lower threshold for induction (and higher velocity of propagation) of cortical spreading depression (CSD, the phenomenon that underlies migraine aura and can also trigger migraine headache). Analysis of synaptic transmission in cortical slices and in microcultures of cortical neurons revealed enhanced excitatory neurotransmission due to increased probability of glutamate release at pyramidal cell synapses of FHM1 KI mice. Using an in vitro model of CSD, a causative link between enhanced glutamate release and CSD facilitation has been established. In contrast with the enhanced excitatory transmission, inhibitory neurotransmission at cortical fast-spiking (FS) interneuron synapses of FHM1 KI mice was unaltered, despite being initiated by P/Q-type Ca²⁺ channels. The synapse-specific effect of FHM1 mutations arise from both neuron subtype-specific alterations of the Ca_V2.1 channel and the different duration of the action potentials in pyramidal cells and FS interneurons. The synapse-specific effect of FHM1 mutations point to episodic disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for vulnerability to CSD ignition in migraine.