Migraine is a common but poorly understood sensory circuit disorder. Mouse models of familial hemiplegic migraine (FHM, a rare monogenic form of migraine with aura) show increased susceptibility to cortical spreading depression (CSD, the phenomenon that underlies migraine aura and can activate migraine headache mechanisms), allowing an opportunity to investigate the mechanisms of CSD and migraine onset. In FHM type 2 (FHM2) knock-in mice with reduced expression of astrocytic Na, K-ATPases, the reduced rate of glutamate uptake into astrocytes can account for the facilitation of CSD initiation. Here, we investigated the underlying mechanisms and show that the reduced rate of glutamate clearance in FHM2 mice results in increased amplitude and slowing of rise time and decay of the NMDA receptor (NMDAR) excitatory postsynaptic current (EPSC) elicited in layer 2/3 pyramidal cells by stimulation of neuronal afferents in somatosensory cortex slices. The relative increase in NMDAR activation in FHM2 mice is activity-dependent, being larger after high-frequency compared to low-frequency afferent activity. Inhibition of GluN1-N2B NMDARs, which hardly affected the NMDAR EPSC in wild-type mice, rescued the increased and prolonged activation of NMDARs as well as the facilitation of CSD induction and propagation in FHM2 mice. Our data suggest that the enhanced susceptibility to CSD in FHM2 is mainly due to specific activation of extrasynaptic GluN1-N2B NMDARs and point to these receptors as possible therapeutic targets for prevention of CSD and migraine.