Several forms of hippocampal synaptic plasticity have been shown to require de novo protein synthesis. N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) is the most widely studied cellular model of learning and memory. One form of LTP, long-lasting late-phase LTP (L-LTP), requires both gene transcription and protein translation. Another form of hippocampal synaptic plasticity, metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is of particular interest because it requires rapid translation of preexisting mRNA, bypassing the need for transcription. Do similar signaling pathways couple mGluRs and NMDA receptors to the translation machinery during mGluR-LTD and L-LTP, respectively? This appears to be the case for cap-dependent and 5'TOP translation. In the past several years, several laboratories, including my laboratory, have shown that two key signaling pathways regulate cap-dependent and 5'TOP translation during both mGluR-LTD and L-LTP. These findings have generated much excitement because they were the first demonstration of biochemical regulation of translation during hippocampal synaptic plasticity. We plan to address two critical questions to gain a more complete understanding of the translational control mechanisms operating during hippocampal synaptic plasticity. First, is cap-dependent translation similarly regulated during mGluR-LTD and L-LTP? Second, is eIF2a phosphorylation and are uORF-containing mRNAs differentially translated during mGluR-LTD versus L-LTP? These questions will be addressed by utilizing the powerful multidisciplinary combination of electrophysiological recording techniques, Western blot analyses, direct enzymatic assays, subcellular fractionation, immunocytochemistry, and genetically-modified mice to study mGluR-LTD and L-LTP, as well as learning and memory. The results of our experiments will provide important information concerning the signaling mechanisms that underlie not only synaptic plasticity, but also learning and memory processes. Finally, these studies will generate critical information about the biochemical basis of the alterations in synaptic plasticity that occur in fragile X syndrome and tuberous sclerosis complex, mental retardation syndromes that have altered translation.
The overall goal of the proposed work in this application is identify the biochemical mechanisms responsible for initiating protein synthesis during synaptic plasticity and memory, and whether these mechanisms are altered and can be reversed in mouse models of fragile X syndrome (FXS) and tuberous sclerosis complex (TSC). It is estimated that 1 in 150 children in the United States are born with autism spectrum disorders (ASDs). The prevalence of ASDs in FXS has been estimated to be 15-30%, and conversely, up to 5% of children with ASDs have been found to have FXS. TSC also has a high prevalence of ASDs, estimated at 25-60%. We have proposed experiments to determine the specific mechanisms that regulate protein synthesis during multiple forms of hippocampal synaptic plasticity in normal mice, and will use pharmacological and genetic approaches to reverse alterations in synaptic plasticity in mice that model FXS and TSC. These studies have the potential to identify several new therapeutic targets for the treatment of FXS and TSC, and by extension, ASDs.
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