Kinase modulation of NMDA receptors: PKC pathways and LTP of the NMDA component in the hippocampus

The N-methyl-D-aspartate (NMDA)-type glutamate receptor is a critical component of many neuronal processes including learning and memory. The cellular model for learning and memory involve phenomenon known as long-term potentiation (LTP) and long-term depression. These processes have been shown to be NMDA-receptor dependent in certain areas of the hippocampus. Phosphorylation of NMDA receptor subunits provides a mechanism to modulate receptor function and many kinases have been shown to upregulate currents through the NMDA receptor by means of phosphorylation. A number of kinases have also been implicated as being important for LTP, a process that is driven by AMPA as well as NMDA receptors (AMPA LTP).; The following results show that isolated NMDA receptor currents in the hippocampal CA3-CA1 synapse also undergo their own LTP and LTD (LTP/LTD of the NMDA component). This plasticity of the isolated NMDA receptor component in the hippocampus is shown to be mediated by a number of protein kinases and exhibit characteristics that indicate that LTP and LTD of the NMDA component may be different from AMPA LTP and LTD.; Protein kinase C (PKC) has been shown to potentiate NMDA receptor currents. It has also been shown that direct PKC phosphorylation of the NMDA receptor subunits, NR2A and NR2B, leads to a modulation of receptor function. Src tyrosine kinase is also known to upregulate NMDA receptors and is highly expressed in the CA1 region of the hippocampus. Calcium calmodulin-dependent protein kinase II (CaMKII) has been shown to be a key component in the AMPA LTP and is known to phosphorylate the NMDA receptor. The following results indicate that PKC-mediated potentiation of NMDA receptor currents in Xenopus oocytes is through, not only direct PKC-driven phosphorylation of the receptor subunits, but also through an indirect pathway that involves activation of another kinase. Proline-rich tyrosine kinase 2 (Pyk2) has been shown to be activated by PKC as well as has been shown to be an activator of Src tyrosine kinase. The following results indicate that a portion of the PKC-mediated potentiation of NMDA receptor currents is through activation of Pyk2 kinase.; The following results indicate that PKC, Src and CaMKII mediate LTP of the NMDA component in the CA3-CA1 synapse of the rat hippocampus. Further, the subsequent experiments also show that postsynaptic inhibition of any of these kinases reveal an LTD of the NMDA receptor component. This LTD of the NMDA component differs from AMPA LTD in that it is present in conditions under which there are high concentrations of calcium. The following results indicate that postsynaptic inhibition of PKC as well as an induction of LTD of the NMDA component results in an attenuated level of AMPA LTP. Taken together, these studies show that plasticity of isolated synaptic NMDA receptor currents is mediated by PKC, Src, and CaMKII. The overall level of NMDA receptor plasticity is also shown to determine the overall level of AMPA LTP, or synaptic plasticity.