It is generally recognized that the primary cause of migraine lies in the brain and that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura. In animal studies, a single CSD can lead to prolonged activation of meningeal nociceptors and central trigeminovascular neurons, suggesting that CSD may also initiate the headache mechanisms. Gain-of-function mutations in the CaV2.1 (P/Q-type) calcium channel and loss-of-function mutations in the alpha2 Na/K-ATPase cause a rare subtype of migraine with aura: familial hemiplegic migraine (FHM1 and FHM2, respectively). Cav2.1 channels are located in presynaptic terminals and somatodendritic membranes throughout the brain and play a prominent role in initiating action potential-evoked neurotransmitter release at central nervous system synapses. The alpha2 Na/K ATPase is expressed primarily in neurons during embryonic development and at time of birth but almost exclusively in astrocytes in the adult brain. Knockin (KI) mouse models carrying FHM1 or FHM2 mutations show a lower threshold for CSD induction and a higher velocity of CSD propagation. In this lecture I summarize our studies in FHM1 KI mice that reveal the functional consequences of FHM1 mutations on i) the neuronal Ca current in different cortical and trigeminal ganglion (TG) neurons, ii) the unitary synaptic transmission and short-term synaptic plasticity at the main synapses of the cortical microcircuit involving pyramidal cells, fast spiking interneurons and somatostatin-expressing interneurons, iii) the balance between the total excitatory and inhibitory synaptic drive in individual cortical neurons during spontaneous cortical network activity, and iv) CGRP release in the TG and dura. The insights into the pathophysiology of migraine obtained from these studies will be discussed. In general, our data strengthen the view of CSD as a key migraine trigger and point to episodic disruption of the excitatory-inhibitory balance and neuronal hyperactivity as the basis for vulnerability to CSD ignition in migraine.