BACKGROUND AND PURPOSE: dowuregulation of the tumor suppressor, phosphatase and (tla)sin homolog deleted on chromosome 10 (PTEN), is thought to be a novel neuroprotective strategy in ischemic stroke,but the underlying mechanisms remain unclear.In this study, we aimed to validate the use of PTEN regulation of gamma-aminobutyric acid subtype A receptors (GABA(A)Rs) as a molecular target for the treatment of ischemic stroke.Because suppression of GABA(A)Rs contributes to ischemic neuron death, describing the intracellular signaling that interacts with GABA(A)Rs in ischemic neurons would provide a molecular basis for novel stroke therapies.METHODS: we measured surface GABA(A)R expression by immunocytochemical labeling and surface (protein) biotinylation assay.Knockdown and overexpression approaches were used to test the effects of PTEN on the expression and function of GABA(A)Rs.Neuronal death was detected in both in vitro and in vivo stroke models.RESULTS: the knockdown and overexpression approaches provided the first evidence that PTEN negatively regulated membrane expression and function of GABA(A)Rs in rat hippocampal neurons.Importantly, we demonstrated that a PTEN inhibitor prevented the reduction of surface GABA(A)Rs in injured hippocampal neurons subjected to oxygen-glucose deprivation, an in vitro insult that mimics ischemic injury, whereas a GABA(A)R antagonist significantly reduced this PTEN inhibitor-induced neuroprotection in both the in vitro and in vivo ischemic stroke models.CONCLUSIONS: our study provides direct evidence that downregulation of PTEN protects against ischemic neuron death by preserving GABA(A)R function.Targeting this pathway may be an effective strategy for development of selective, potent stroke treatments.