Stroke induced by middle cerebral artery occlusion (MCAO) is a common cause of adult disability leading to motor-sensory disturbances and cognitive impairment.It is generally accepted that cognitive impairment in stroke patients caused by MCAO results from damage to the cerebral cortex rather than the hippocampus, because the middle cerebral artery does not supply blood to the hippocampus.Here we provide the first evidence that patients with exclusively unilateral MCAO show hippocampal damage characterized by an infarct size-independent atrophy and alterations in neuronal and glial metabolites in the ipsilateral hippocampus as assessed by MRI, in parallel with a significant decline in cognitive function.Rodent MCAO also induces delayed shrinkage and pyramidal neuronal death in the ipsilateral hippocampus and an impairment of hippocampal-dependent spatial memory.ExtracelluIar glutamate and pyramidal neuronal intracellular calcium levels were significantly elevated and spreading depression waves were observed in the hippocampus which correlated with neuronal damage.Blocking gap junctional communication (GJC) with carbenoxolone or down-regulation Cx43 significantly increased the survival of the pyramidal neurons in the ipsilateral hippocampus and improved behavioral scores.Furthermore, Cx43 heterozygous mice showed reduced shrinkage and metabolites abnormality in ipsilateral hippocampus after MCAO.These results suggest a significant role of astroglial GJC in MCAO-induced remote hippocampal damage and cognitive impairment.