Activation of extrasynaptic NMDA receptors (exNMDARs) initiates the neuronal death.Although growing evidence suggests the activation of exNMDARs in some pathological models, no direct evidence demonstrated their activation during ischemia.We have detected the exNMDAR currents in rat hippocampal neurons during ischemia in situ by electrophysiological recording.BAPTA dialysis of astrocytic Ca2+ inhibited the activation of exNMDARs.By uncaging Ca2+ in individual astrocyte, we found that ischemia facilitated the propagation of astrocytic Ca2+ waves, which were inhibited by gap junction blocker carbenoxolone (CBX).CBX also inhibited the astrocytic Ca2+ activity and activation of exNMDARs induced by ischemia.Furthermore, CBX reduced the infarct volume in in vivo ischemic model, suggesting the neuroprotective effect of inhibiting the Ca2+activity of astrocytic network.These results indicate that Ca2+ activity of the astrocytic network contributes to the activation of exNMDARs in hippocampal neurons and ischemic brain damage.