Tissue-type plasminogen activator is a homeostatic regulator of synaptic function in the central nervous system

Abstract

Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons. Once in the synaptic cleft this tPA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles, and regulates the postsynaptic response to the presynaptic release of glutamate. Indeed, tPA has a bidirectional effect on the composition of the postsynaptic density (PSD) that does not require plasmin generation or the presynaptic release of glutamate, but varies according to the baseline level of neuronal activity. Hence, in inactive neurons tPA induces phosphorylation and accumulation in the PSD of the Ca²⁺/calmodulin-dependent protein kinase IIα (pCaMKIIα), followed by pCaMKIIα-induced phosphorylation and synaptic recruitment of GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast, in active neurons with increased levels of pCaMKIIα in the PSD tPA induces pCaMKIIα and pGluR1 dephosphorylation and their subsequent removal from the PSD. These effects require active synaptic N-methyl-D-aspartate (NMDA) receptors and cyclin-dependent kinase 5 (Cdk5)-induced phosphorylation of the protein phosphatase 1 (PP1) at T320. These data indicate that tPA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCaMKIIα /PP1 switch in the PSD.

Keywords: Ca2+/calmodulin-dependent protein kinase; homeostatic plasticity; plasmin; post-synaptic density; protein phosphatase 1; tissue-type plasminogen activator (tPA).

Figure 1

Tissue-type plasminogen activator (tPA) induces homeostatic plasticity in cerebral cortical neurons. tPA induces bidirectional changes in the structure and protein composition of the postsynaptic density (PSD) via its ability to regulate the protein phosphatases (PP) 1/Calmodulin-dependent protein kinase II (pCaMKII) switch. (A) In inactive neurons with low baseline expression of pCaMKIIa, tPA activates the kinase by inducing its phosphorylation at T286 in a Ca²⁺- and N-methyl-D-aspartate receptor (NMDAR)-dependent manner, followed by its subsequent translocation to the postsynaptic density where it induces the phosphorylation and synaptic recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, thus converting silent into active synapses. When activated by p35, cyclin-dependent kinase 5 (Cdk5) induces the PP1 phosphorylation at T320, an event that inactivates PP1 and thereby allows the phosphorylation and synaptic accumulation of pCaMKII. (B) In overactive neurons, tPA prevents p35-induced Cdk5 activation and Cdk5-induced PP1 inactivation by T320 phosphorylation. The active phosphatase is then able to dephosphorylate pCaMKIIa preventing its accumulation in the postsynaptic density (PSD) and abrogating the effect of pCaMKIIa on the synaptic recruitment of GluR1-containing AMPA receptors.