Increasing evidence indicates that neurosteroid 17beta-Estradiol (E2), a type of female sex hormone, has a neuroprotective effect against cerebral injury. However, it remains unknown whether E2 can also protect the hippocampal CA1 neurons from functional deficits in synaptic transmission and plasticity caused by ischemia. To address this issue, adult male Wistar rats were subjected to mild global cerebral ischemia created by four-vessel occlusion (4VO) for 10min, and the effects of E2 administration against the ischemic injury were investigated. The electrophysiological properties of Schaffer collateral-CA1 synapses were examined 7days after ischemia by applying a real-time optical recording technique to the hippocampal slices stained with a voltage-sensitive dye (RH482). The ischemic brain showed a decreased basal synaptic transmission and an impairment of LTP induction, but no alteration in paired-pulse facilitation. The administration of E2 (1mg/kg) 3h before ischemia was able to protect CA1 neurons from these ischemia-induced synaptic dysfunctions. The estrogen receptor-alpha (ERalpha) selective agonist, propyl pyrazole triol (PPT, 2mg/kg), exerted a similar protective effect, but the estrogen receptor-beta (ERbeta) agonist, diarylpropiolnitrile (DPN, 8mg/kg), failed to do so. A histological examination revealed that the transient global cerebral ischemia markedly reduced the density of pyramidal neurons in the CA1 region. The cell loss was significantly attenuated by E2 and PPT but not by DPN, as observed in synaptic functions. These findings suggest that E2 can protect neurons not only from cell death but also from functional damages due to a relatively mild degree of transient cerebral ischemia, and this effect is mediated by ERalpha, but not by ERbeta.