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Objective It is well known that neurons in the CA3 and dentate gyrus (DG) subfields of the hippocampus are tolerant to short period of ischemia which is usually lethal to pyramidal neurons in hippocampal CA1 subfield.The present study was undertaken to clarify whether the inherent higher tolerance of neurons in CA3 and DG to ischemia is associated with glial glutamate transporter-1 (GLT-1) in rats.Methods Western blot analysis and immunohistochemistry assay were used to detect the expression of GLT-1 protein.DHK and GLT-1 AS-ODNs were used to inhibit the function and expression of GLT-1.Thionin staining was used for neuropathological evaluation.Results (1) Western blot analysis and immunohistochemistry assay showed that the basal expression of GLT-1 in both CA3 and DG was much higher than that in CA1 subfield.(2) Mild global brain ischemia for 8 min induced delayed death of almost all CA 1 pyramidal neurons and marked GLT-1 down-regulation in the CA1 subfield, but it had no effect on the neuronal survival in either CA3 or DG and induced GLT-1 up-regulation in both areas.When the global brain ischemia was prolonged to 25 min, neuronal death was clearly observed in CA3 and DG accompanied with down-regulation of GLT-1 expression in both areas.(3)After down-regulating GLT-1 expression and function by its antisense oligodeoxynucleotides or inhibiting GLT-1 function by dihydrokainate, an inhibitor of GLT-1, the mild global brain ischemia for 8 min, which usually was not lethal to CA3 and DG neurons, induced the neuronal death in CA3 and DG subfields.Conclusion The higher expression of GLT-1 in CA3 and DG contributes to their inherent tolerance to ischemia.