Translation Regulation in Hippocampal LTP and LTD

海马突触可塑性的几种形式已被证明需要从头蛋白质合成。N-甲基-D-天冬氨酸（NMDA）受体依赖的长时程增强（LTP）是研究最广泛的学习记忆细胞模型。LTP的一种形式，持久的晚期LTP（L-LTP），需要基因转录和蛋白质翻译。另一种形式的海马突触可塑性，代谢型谷氨酸受体依赖性长期抑制（mGluR-LTD）是特别感兴趣的，因为它需要快速翻译预先存在的mRNA，绕过转录的需要。在mGluR-LTD和L-LTP过程中，mGluRs和NMDA受体是否分别通过类似的信号通路与翻译机制相偶联？这似乎是帽依赖性和5 'TOP翻译的情况。在过去的几年里，包括我的实验室在内的几个实验室已经表明，在mGluR-LTD和L-LTP过程中，两种关键的信号通路调节帽依赖性和5 'TOP翻译。这些发现引起了极大的兴奋，因为它们首次证明了海马突触可塑性期间翻译的生化调节。我们计划解决两个关键问题，以获得更完整的理解海马突触可塑性的翻译控制机制。首先，在mGluR-LTD和L-LTP过程中，帽依赖性翻译是否受到类似的调节？第二，eIF 2磷酸化和uORF的mRNA差异翻译过程中mGluR-LTD与L-LTP？这些问题将通过利用强大的多学科组合的电生理记录技术，蛋白质印迹分析，直接酶测定，亚细胞分级分离，免疫细胞化学，和基因修饰的小鼠研究mGluR-LTD和L-LTP，以及学习和记忆来解决。我们的实验结果将提供重要的信息有关的信号机制，不仅是突触可塑性，而且学习和记忆过程。最后，这些研究将产生关键信息的生化基础上发生在脆性X综合征和结节性硬化症，精神发育迟滞综合征，改变了翻译的突触可塑性的改变。

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 eIF2 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.