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Glutamate NMDARs (N-methyl-D-aspartate receptors) play a major role in the initiation of ischemic brain damage. However, NMDAR antagonists have no protective effects in stroke patients, possibly because they impair physiological functions of NMDARs. α2δ-1 (encoded by Cacna2d1) is strongly expressed in many brain regions. We determined the contribution of α2δ-1 to NMDAR hyperactivity and brain injury induced by ischemia and reperfusion.Mice were subjected to 90 minutes of middle cerebral artery occlusion followed by 24 hours of reperfusion. Neurological deficits, brain infarct volumes, and calpain/caspase-3 activity in brain tissues were measured. NMDAR activity of hippocampal CA1 neurons was measured in an in vitro ischemic model.Middle cerebral artery occlusion increased α2δ-1 protein glycosylation in the cerebral cortex, hippocampus, and striatum. Coimmunoprecipitation showed that ischemia rapidly enhanced the α2δ-1–NMDAR physical interaction in the mouse brain tissue. Inhibiting α2δ-1 with gabapentin, uncoupling the α2δ-1–NMDAR interaction with an α2δ-1 C terminus–interfering peptide, or genetically ablating Cacna2d1 had no effect on basal NMDAR currents but strikingly abolished oxygen-glucose deprivation–induced NMDAR hyperactivity in hippocampal CA1 neurons. Systemic treatment with gabapentin or α2δ-1 C-terminus–interfering peptide or Cacna2d1 genetic knock-out reduced middle cerebral artery occlusion–induced infarct volumes, neurological deficit scores, and calpain/caspase-3 activation in brain tissues.α2δ-1 is essential for brain ischemia–induced neuronal NMDAR hyperactivity, and α2δ-1–bound NMDARs mediate brain damage caused by cerebral ischemia. Targeting α2δ-1–bound NMDARs, without impairing physiological α2δ-1–free NMDARs, may be a promising strategy for treating ischemic stroke.