NMDA receptor activations produce substantial elevations in intracellular calcium levels, which initiate signaling cascades critical for normal ad pathological brain processes. These include normal synaptic development and plasticity, as well as psychiatric conditions such as addiction and chronic pain, schizophrenia, and neuropathologies such as stroke and Alzheimer's disease. Until recently it was assumed that the amount of calcium in the NMDA receptor current is fixed and controlled solely by gating modulators and channel blockers. This project investigates a newly reported modulatory mechanism by which intracellular signaling cascades can change in a reversible fashion the amount of calcium in the NMDA receptor current. This work seeks to identify the molecular determinants and mechanisms responsible for this new modulation. The resulting knowledge will inform novel strategies to address dysfunctions and pathologies where NMDA receptor- mediated calcium is a cause or an aggravating factor.
The calcium fluxes resulting from NMDA receptor activity are essential to the roles played by these receptors in the physiology of central excitatory synapses and their dysregulation has been implicated in the etiology of psychiatric disorders such as schizophrenia, addiction and chronic pain. In addition, NMDA receptor-mediated calcium influx is the major conduit of glutamate excitotoxicity, a principal mechanism in acute and chronic neurodegenerative conditions such as stroke, Alzheimer, Parkinson, and Huntington's diseases. Results from this application will afford a better understanding of the mechanisms that control NMDA receptor-mediated calcium fluxes and thus will inform more effective strategies to address dysfunctions and pathologies caused by inappropriate calcium influx through NMDA receptors.
