This proposal is designed to investigate the biochemical signaling mechanisms underlying metabotropic glutamate receptor-dependent (mGluR) long-term depression (LTD) and late-phase long-term potentiation (L-LTP) in area CA1 of the mouse hippocampus. These forms of synaptic plasticity previously have been shown to be dependent on new protein synthesis. However, virtually nothing is known about the signaling cascades that couple either mGluRs or N-methyl-D-aspartate (NMDA) receptors to the protein translation machinery during these forms of plasticity. If both mGluR-LTD and L-LTP are both dependent on protein synthesis, then several critical questions arise. Are the same signaling pathways required to couple mGluRs and NMDA receptors to the translation machinery during mGluR-LTD and L-LTP, respectively? Are there mRNAs that are preferentially translated during mGluR-LTD versus L-LTP? Using a combination of biochemical, immunocytochemical, pharmacological, and electrophysiological techniques, as well as genetically-modified mice, we propose to 1) test the hypothesis that cap-dependent translation signaling pathways are involved in mGluR-dependent LTD and late-phase LTP, 2) test the hypothesis that S6-directed translation signaling pathways are involved in mGluR-dependent LTD and late-phase LTP, and 3) test the hypothesis that fragile X mental retardation protein is involved in the regulation of mGluR-dependent LTD but not late-phase LTP, and that translation is regulated improperly during mGluR-dependent LTD in mouse models of fragile X mental retardation. These studies should provide insights into the signaling cascades that couple mGluRs and NMDA receptors to protein translation forms of synaptic plasticity that may be important for learning and memory. These studies may also elucidate unique signaling cascades in the hippocampus that will be critical for understanding the behavioral abnormalities and memory impairments associated with fragile X mental retardation.
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