Activation of the Gq coupled metabotropic glutamate receptors (Group 1 mGluRs) induce long-term plasticity of neuronal and synaptic function which is mediated through direct regulation of new protein synthesis. Consequently, the group 1 mGluRs, mGluR1 and mGluR5 are implicated many long-term behavioral adaptions of brain function including postnatal cortical map formation, learning and memory, chronic pain and drug addiction. Elucidating the basic mechanisms of how mGluRs and other Gq coupled neurotransmitter receptors induce plasticity and how these new proteins alter synapse function is essential to understanding the neurobiological basis of these behaviors. The significance of mGluR- dependent plasticity to human cognitive function is highlighted by the recent findings of enhanced or unregulated mGluR-and protein synthesis dependent plasticity in the mouse model of fragile X syndrome (Fmr1 KO mice), the most common inherited form of mental retardation in humans. We have discovered and characterized a form of long-term synaptic depression in hippocampal area CA1 induced by group 1 mGluRs which relies on rapid (within minutes) protein synthesis in dendrites (mGluR-LTD). Furthermore, we have found that the mechanisms of mGluR-LTD are altered in Fmr1 KO mice. This proposal focuses on determining how mGluRs induce LTD and regulate protein synthesis machinery and how new proteins lead to persistent changes at synapses. Based on our new findings, we hypothesize and propose experiments to test if other Gq coupled neurotransmitter receptors induce LTD through similar mechanisms as group 1 mGluRs. From the knowledge gained from the study of the basic mechanisms of mGluR-LTD in normal rodents, we propose experiments to examine how and why mGluR-dependent plasticity is altered in Fmr1 KO mice. 1: Determine the role of Homer isoforms in mGluR-and protein synthesis dependent LTD mechanisms. 2: Determine mechanism for persistent decreases in AMPAR surface expression induced by mGluRs. 3: Explore the role of other Gq coupled receptors in protein synthesis dependent LTD .4: Role of Homer interactions and other Gq coupled receptors in LTD in Fmr1 KO mice.
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