Translation Regulation in Hippocampal LTP and LTD

海马 LTP 和 LTD 的翻译调节

• 批准号: 7896528
• 负责人: Eric Klann
• 金额: $ 37.21万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896528
• 关键词: Address; Behavioral; Biochemical; Biological Assay; Bypass; Cell Fractionation; Cell model; Child; Dendrites; Dendritic Spines; Fragile X Syndrome; Genetic; Genetic Transcription; Genetic Translation; Goals; High Prevalence; Hippocampus (Brain); Laboratories; Learning; Long-Term Depression; Long-Term Potentiation; Memory; Mental Retardation; Messenger RNA; Metabotropic Glutamate Receptors; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Neurotransmitter Receptor; Phase; Phosphorylation; Polyribosomes; Prevalence; Process; Protein Biosynthesis; Proteins; Regulation; Ribosomes; Signal Pathway; Signal Transduction; Synapses; Synaptic plasticity; Syndrome; Techniques; Testing; Translating; Translation Initiation; Translations; Tuberous sclerosis protein complex; United States; Western Blotting; Work; autism spectrum disorder; base; immunocytochemistry; insight; interest; memory process; mouse model; multidisciplinary; new therapeutic target; research study; translation factor

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.

海马区突触可塑性的几种形式已经被证明需要从头合成蛋白质。N-甲基-D-天冬氨酸(NMDA)受体依赖的长时程增强(LTP)是目前研究最广泛的学习记忆细胞模型。LTP的一种形式是长效晚期LTP(L-LTP)，既需要基因转录，也需要蛋白质翻译。另一种形式的海马突触可塑性，代谢性谷氨酸受体依赖的长期抑制(mGluR-LTD)特别令人感兴趣，因为它需要快速翻译先前存在的mRNA，绕过转录的需要。在mGluR-LTD和L-LTP过程中，是否有类似的信号通路将mGluR和NMDA受体分别偶联到翻译机制上？这似乎是依赖大写字母和5‘顶部平移的情况。在过去的几年里，包括我的实验室在内的几个实验室已经证明，在mGluR-LTD和L-LTP过程中，有两个关键的信号通路调节帽依赖和5‘顶端翻译。这些发现引起了许多人的兴奋，因为他们首次证明了在海马区突触可塑性过程中翻译的生化调节。我们计划解决两个关键问题，以更全面地了解海马区突触可塑性过程中的翻译控制机制。首先，大小写依赖的翻译在mGluR-Ltd.和L-LTP中是否受到类似的监管？第二，在mGluR-LTD和L-LTP期间，eIF2是否被磷酸化，以及含有uORF的mRNAs是否有差异翻译？这些问题将通过利用电生理记录技术、蛋白质印迹分析、直接酶分析、亚细胞分离、免疫细胞化学和转基因小鼠的强大多学科组合来解决，以研究mGluR-LTD和L-LTP以及学习和记忆。我们的实验结果将提供有关信号机制的重要信息，这些机制不仅是突触可塑性的基础，也是学习和记忆过程的基础。最后，这些研究将产生关于脆性X综合征和结节性硬化症的突触可塑性改变的生化基础的关键信息，这些综合征是改变翻译的精神发育迟滞综合征。