EXCITOTOXIN-INDUCED NEURONAL DEGENERATION AND SEIZURE ARE MEDIATED BYTISSUE-PLASMINOGEN ACTIVATOR

NEURONAL degeneration in the hippocampus, a region of the brain import ant for acquisition of memory in humans, occurs in various pathologica l conditions, including Alzheimer's disease, brain ischaemia and epile psy. When neuronal activity is stimulated in the adult rat and mouse h ippocampus, tissue plasminogen activator (tPA), a serine protease that converts inactive plasminogen to the active protease plasmin, is tran scriptionally induced(1,2). The activity of tPA in neural tissue is co rrelated with neurite outgrowth(3), regeneration(4) and migration(5), suggesting that it might be involved in neuronal plasticity. Here we s how that tPA is produced primarily by microglia in the hippocampus. Us ing excitotoxins to induce neuronal cell loss, we demonstrate that tPA -deficient mice are resistant to neuronal degeneration. These mice are also less susceptible to pharmacologically induced seizures than wild -type mice. These findings identify a role for tPA in neuronal degener ation and seizure.