The distribution of tPA and its role in the hippocampus. (a) tPA immunohistochemistry (red) with superimposed scheme of synaptic input from the amygdala and the three-synaptic hippocampal neuronal circuit (yellow). tPA immunoreactivity is observed almost exclusively in the mossy fiber pathway (24), suggesting that it plays a particularly important role in conducting impulses from the mossy fibers to the Schaffer collaterals. Neuronal cell bodies are counterstained with 4,6-diamino-2-phenylindole (blue). CA1 and CA3, regions of the hippocampus; DG, dentate gyrus. (b) Schematic representation of a hippocampal synapse, showing the putative mechanism of tPA action at that site. tPA (gray) is released from the axon terminal upon neuronal depolarization, where it facilitates spreading of an impulse to the postsynaptic site by activating NMDA receptors (green). During excitotoxic challenge, excessive amounts of tPA could also activate plasminogen (blue) to trigger neuronal death by degrading laminin (11). tPA activity could be inhibited by neuroserpin (yellow), thus attenuating seizure spreading and cell death.