The group 1 metabotropic, or G-protein coupled, glutamate receptors (mGluRs) induced long-term changes in neuronal function. Group 1 mGluRs, in particular, has been implicated in many behaviors which are a result of persistent alterations in brain neuronal circuitry, such as learning and memory, drug addiction, chronic pain, and cortical development. Recent work has demonstrated that mGluR activation induces persistent changes in neurons by a direct regulation of protein synthesis. For example, activation of group 1 mGluRs with the selective agonist, dihydroxyphenylglycine (DHPG), or synaptic stimulation, induces a robust and long-term depression (mGluR-LTD) of excitatory synaptic transmission in hippocampal area CA1 neurons. The synaptic mechanism that underlies LTD is thought to be the rapid internalization of the postsynaptic AMPA subtype of glutamate receptors, the receptors responsible for synaptic transmission at the CA1 synapse. Remarkably, the persistence of mGluR-LTD and AMPAR internalization is mediated by the rapid protein synthesis at hippocampal dendrites. Although the existence of dendritic polyribosomes has been known for sometime, virtually nothing is known about how synaptic protein synthesis is regulated by group 1 mGluRs, or how these new proteins alter synaptic function. Furthermore, there has been no functional role ascribed to mGluR dependent LTD in the forebrain. The main objective of this work is to determine the cellular mechanisms of mGluR-dependent regulation of synaptic strength and investigate possible functional roles for mGluR-LTD. Briefly, the specific aims of the proposed research are as follows: 1: Investigate candidate cellular mechanisms in synaptically and pharmacologically induced mGluR-dependent synaptic plasticity. 2: Identify regulatory mechanisms of protein synthesis activated by mGluRs and test their functional role in mGluR-dependent synaptic plasticity. 3: Determine developmental changes in pre- and postsynaptic mechanisms of mGluR-LTD expression. 4: Evaluate the role of group 1mGluRs in synapse development and maturation.
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