Translation Regulation in Hippocampal LTP and LTD

描述(申请人提供)：本研究旨在研究小鼠海马区代谢性谷氨酸受体依赖(MGluR)长时程增强(LTD)和晚期长时程增强(L-LTP)的生化信号机制。这些形式的突触可塑性之前已经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)受体耦合到蛋白质翻译机制的信号级联几乎一无所知。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，mGluR和NMDA受体分别连接到翻译机制是否需要相同的信号通路？是否存在在mGluR-LTD和L-LTP期间优先翻译的mRNAs？结合生化、免疫细胞化学、药理学和电生理学技术，以及转基因小鼠，我们建议1)检验帽依赖的翻译信号通路参与mGluR依赖的LTD和晚期LTP的假说，2)检验S6定向的翻译信号通路参与mGluR依赖的LTD和晚期LTP的假说，3)在脆性X智力低下的小鼠模型中检验脆性X智力低下蛋白参与mGluR依赖的LTD的调节而不是晚期LTP的假说，以及翻译在mGluR依赖的LTP中调控不当的假说。这些研究应该为mGluRs和NMDA受体与突触可塑性的蛋白质翻译形式之间的信号级联提供洞察力，突触可塑性可能对学习和记忆至关重要。这些研究还可能阐明海马区独特的信号级联，这对于理解与脆性X智力低下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.