Tissue-Plasminogen Activator Is Induced as an Immediate-Early Gene DuringSeizure, Kindling and Long-Term Potentiation

摘要

Activity-dependent genes in brain have been identified using differentialscreening of hippocampal cDNA library from rats exposed to metrazol seizures under conditions of superconduction. Five immediate-early genes whose expression is elevated by neural activity were identified. Three of these genes have not been described before. A fourth gene encodes a previously described nerve-growth factor-inducible protein of unknown function. We focus here on the fifth gene, which we have identified as a tissue-plasminogen activator (tPA), an extracellular serine protease. tPA mRNA is induced in different ways by three activity-dependent events: metrazol triggered convulsions that increase expression throughout the brain; kindling stimulation of the perforant path to induce an afterdischarge that leads to an increase bilaterally throughout the hippocampus; brief high-frequency stimulation of the perforant path that produces longterm potentiation (LTP) that increases tPA mRNA in the granule cells of the dentate gyrus ipsilateral to the stimulated site. This restricted expression induced by LTP was blocked by the NMDA antagonist, MK-801, suggesting that tPA expression and LTP involve similar inductive mechanisms. Stimuli that evoke kindling and LTP induce morphological changes in hippocampal neurons. Since tPA is released from the growth cone, its increased expression may play a role in structural changes that accompany activity-dependent plasticity.