Objective This study was undertaken to determine the role of glial glutamate transporter (GLT)-1 a, one of splice variants of GLT-1, in the induction of brain ischemic tolerance by cerebral ischemic preconditioning (CIP) in a rat global cerebral ischemic model.Methods The expression of GLT-1 a protein and mRNA in the CA 1 hippocampus was observed by using western blotting analysis, immunohistochemistry and RT-PCR.The appearance of neuron and the glutamate concentration in the CA1 hippocampus was studied by using neuropathological evaluation and in vivo brain microdialysis combined with HPLC.Results (1) CIP induced a significant up-regulation of the GLT-1 a expression in the CA1 hippocampus in a time course corresponding to that of neuroprotection of CIP against brain ischemia.Severe brain ischemia for 8 min induced delayed down-regulation of GLT-1a, obvious increase in glutamate concentration and delayed neuronal death of the pyramidal neurons in the CA1 hippocampus.When the animals were pretreated with CIP before the severe ischemia, the above changes induced normally by the severe ischemia were effectively prevented.(2) The preventive effect of CIP on the above changes was significantly inhibited by intracerebroventricular administration of GLT-1a AS-ODNs which has been proved to specifically inhibit the expression of GLT-1 a protein and mRNA.(3) The concentration of aspartate and GABA was also elevated after severe brain ischemic insult.But the CIP had no effect on the elevated aspartate concentration and induced a further elevation in the GABA concentration.Conclusion GLT-1a participates in the acquirement of brain ischemic tolerance induced by CIP in rats.