Glutamate is the major excitatory neurotransmitter in the hippocampus and seems to be involved in the many normal and pathological processes that occur in this area. Therefore, understanding mechanisms of glutamate action could be important to understanding both normal and pathologic hippocampal functions. Glutamate acts on ionotropic (iGluRs), and metabotropic (mGluRs) glutamate receptors. Activation of mGluRs, possibly mGluR5, can potentiate the effects of NMDA receptors, an iGluR, in the hippocampus. Interestingly, responses thought to be mediated by mGluR5 can be potentiated by the activation of NMDA receptors.This reciprocal regulation between MGluRs5 and NMDA receptors could play an important role in regulating forms of hippocampal synaptic plasticity and could contribute to pathological responses seen in the hippocampus. Several studies have focused on mechanisms of mGluR-activated chant in NMDA receptor function but, little is known about the mechanisms by which NMDA receptor activation might potentiate mGluR-mediated responses. Previous studies have shown that mGluR5 is rapidly desensitized by a protein kinase C (PKC)-dependent mechanism, possibly by phosphorylation of a serine residue on mGluR5. Our preliminary studies that suggest that activation of NMDA receptors may reverse agonist-induced desensitization of mGluR5. These data led us to postulate that NMDA receptor activation potentiates mGluR5-mediated responses by activation of a phosphatase and dephosphorylation of the site on mGluR5 involved in desensitization of this receptor. We propose a series of studies employing a combination of electrophysiology, immunology and molecular biology to rigorously test this hypothesis.
