The requirement of protein and messenger RNA synthesis for long-term memory suggests that neural activity induced by learning initiates a cascade of gene expression. Here we use differential screening to identify five immediate-early genes induced by neuronal activity. One of these is tissue-plasminogen activator (tPA), an extracellular serine protease, which is induced with different spatial patterns in the brain by three activity-dependent events: (1) convulsive seizure increases expression of tPA in the whole brain; (2) stimulation of the perforant path produces an epileptiform after-discharge that ultimately leads to kindling increases the levels of tPA throughout the hippocampus bilaterally; and (3) brief high-frequency stimulation of the perforant path that produces long-term potentiation (LTP) causes an NMDA (N-methyl-D-aspartate) receptor-mediated increase in the levels of tPA mRNA which is restricted to the granule cells of the ipsilateral dentate gyrus. As release of tPA is correlated with morphological differentiation, the increased expression of tPA may play a role in the structural changes that accompany activity-dependent plasticity.