Recent experimental observations indicate that tPA plays a key role in the development of neuronal damage that follows cerebral ischemia and excitotoxicity. In an attempt to clarify how tPA favors ischemia-induced neuronal damage, we performed in vitro electrophysiological experiments in striatal slices by using mice selectively lacking this serine protease.We found that tPA ablation did not affect the membrane depolarization of striatal neurons exposed to combined oxygen and glucose deprivation but fully prevented the induction of NMDA-dependent post-ischemic long-term synaptic potentiation. The absence of striatal post-ischemic pote ntiat ion observed in tPA-lacking mice may account for the significant neuroprotection observed in these animals after the occlusion of middle cerebral artery.