Translation Regulation in Hippocampal LTP and LTD

描述（由申请人提供）：本提案旨在研究小鼠海马CA1区代谢性谷氨酸受体依赖（mGluR）长期抑制（LTD）和后期长期增强（L-LTP）的生化信号机制。这些形式的突触可塑性先前已被证明依赖于新的蛋白质合成。然而，在这些形式的可塑性过程中，mGluRs或n -甲基- d -天冬氨酸（NMDA）受体与蛋白质翻译机制之间的信号级联反应几乎一无所知。如果mGluR-LTD和L-LTP都依赖于蛋白质合成，那么就会出现几个关键问题。在mGluR-LTD和L-LTP过程中，mGluRs和NMDA受体是否需要相同的信号通路分别连接到翻译机制？在mGluR-LTD和L-LTP期间是否存在优先翻译的mrna ？结合生物化学、免疫细胞化学、药理学和电生理技术，以及转基因小鼠，我们提出：1)验证帽依赖的翻译信号通路参与mglur依赖性LTD和晚期LTP的假设；2)验证s6导向的翻译信号通路参与mglur依赖性LTD和晚期LTP的假设。3)验证脆性X智力发育迟滞蛋白参与mglur依赖的LTD而不参与后期LTP的调控，并且在脆性X智力发育迟滞小鼠模型中，mglur依赖的LTD期间翻译被不正确调控。这些研究将为mGluRs和NMDA受体耦合到突触可塑性的蛋白质翻译形式的信号级联提供见解，这可能对学习和记忆很重要。这些研究还可能阐明海马体中独特的信号级联，这对于理解与脆性X智力迟钝相关的行为异常和记忆障碍至关重要。

DESCRIPTION (provided by applicant): 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.