Abstract:

Tissue-type plasminogen activator (tPA) is a serine proteinase that catalyzes the conversion of plasminogen (PLG) into plasmin (Pl). For a long time after its discovery it was thought that tPA's main source was the endothelial cell and that therefore its chief role was to generate plasmin in the vascular system. However, this concept was challenged four decades later when a group of investigators identified tPA-catalyzed proteolysis in well-defined areas of the brain, namely the hippocampus, the amygdala, the thalamus and the hypothalamus. Remarkably, subsequent work indicated that neurons but not endothelial cells are the main reservoir of tPA in the central nervous system, and that in the brain tPA has many functions that do not require PLG as a substrate. Interestingly, while most of the studies on neuronal tPA have been performed either with cells cultured from the hippocampus or with hippocampal slices, fewer have investigated whether tPA has a function in cerebral cortical neurons. Research from our laboratory has found that in the cerebral cortex tPA is expressed mainly in axons from clusters of parvalbumin-positive neurons, and that membrane depolarization induces the rapid release of this tPA. To further characterize the axonal expression of tPA, wild-type cerebral cortical neurons were co-stained with antibodies against tPA and bassoon, a protein abundantly expressed in the presynaptic terminal. These studies revealed that approximately one-third of all axonal tPA is found in the axonal bouton. Remarkably, this proportion remained constant throughout all examined axons, suggesting the presence of a mechanism that regulates the translocation of tPA from the axonal shaft into the presynaptic terminal. In summary, the available data indicate that tPA plays a central role as a regulator of synaptic function. According to this model, the release of tPA from cerebral cortical neurons has a neuromodulatory effect on presynaptic function by inducing the anatomical and biochemical changes in the synaptic release site required for the release of excitatory neurotransmitters. Further studies are needed to understand whether this effect requires a receptor for tPA on the surface of the presynaptic terminal.