Local Mechanisms Underlying Synaptic Plasticity

突触可塑性的局部机制

• 批准号: 7749274
• 负责人: ASHOK N HEGDE
• 金额: $ 32.38万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749274
• 关键词: Address; Age; Biological; Biological Models; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Chromatin; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; Data; Dendrites; Disease; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Hippocampus (Brain); Laboratories; Long-Term Potentiation; Maintenance; Mediating; Memory; Memory Loss; Methods; Molecular; N-Methyl-D-Aspartate Receptors; Names; Neurons; Obstruction; Pathway interactions; Phase; Play; Proteasome Inhibition; Proteasome Inhibitor; Protein Biosynthesis; Proteins; Proteolysis; Proteomics; Regulation; Research; Role; Staging; Synapses; Synaptic plasticity; Testing; Transcription Repressor/Corepressor; Translating; Translations; Ubiquitin; Work; base; gene repression; genetic regulatory protein; histone modification; long term memory; multicatalytic endopeptidase complex; neuronal cell body; protein degradation; public health relevance; research study

Description (provided by applicant): Understanding mechanisms by which synapses are modified for long-term memory storage is crucial for explaining normal brain function as well as diseases and disorders of the brain. Many studies have established that new gene expression and new protein synthesis are critical for synaptic changes that underlie long-term memory. Recent studies indicate that proteolysis by the ubiquitin-proteasome pathway plays a critical role in long-term synaptic plasticity. The goal of this proposal is to elucidate the spatial and temporal roles of the proteasome and the interplay between protein synthesis and degradation in long-term synaptic plasticity We will use a highly suitable model system of mammalian long-term synaptic plasticity, late phase long-term potentiation (L-LTP) in the hippocampus. Our results show that inhibition of the proteasome enhances the early, translation-dependent induction part of L-LTP but inhibits the transcription-dependent maintenance phase of L-LTP. Proteasome-mediated enhancement of early part of L-LTP depends on NMDA receptor and cAMP-dependent protein kinase. Our data indicate that proteasome inhibition increases induction of L-LTP by stabilizing the locally synthesized proteins in the dendrites but interferes with local translation at later stages. Our results also show that inhibition of proteasome blocks transcription of brain-derived neurotrophic factor (BDNF), which is a cAMP-responsive element binding protein (CREB)-inducible gene. Furthermore, our results show that proteasome inhibitors block degradation of ATF4, a CREB repressor that is known to suppress L-LTP and memory. Thus, proteasome inhibition appears to block maintenance of L-LTP by hindering CREB-mediated transcription. Our first aim is to investigate the mechanism by which L-LTP induction is enhanced by proteasome inhibition and to identify the newly synthesized proteins stabilized by the proteasome. Under our second aim, we will test the idea that blockade of the proteasome impairs the maintenance of L-LTP by causing a buildup of negative regulators of plasticity such as translation repressors and by hindering transcription in the nucleus. Using a powerful combination of proteomic, molecular biological and electrophysiological studies the proposed experiments will address important, unanswered questions pertaining to the relationship between proteolysis and protein synthesis in long-term synaptic plasticity. PUBLIC HEALTH RELEVANCE: Memories form when connections between nerve cells called synapses change. Recent discoveries show that regulation of proteins in the nerve cells by degradation plays a role in memory. Proteins are degraded by a part of the cell named proteasome when they are tagged by a little molecule called ubiquitin. Protein degradation is abnormal in many diseases and disorders of the brain. This research could help explain the memory loss that occurs in brain diseases and memory loss that happens in old age.

描述（由申请人提供）：了解突触被修改以进行长期记忆存储的机制对于解释正常的大脑功能以及大脑的疾病和紊乱至关重要。许多研究已经证实，新的基因表达和新的蛋白质合成对于长期记忆的突触变化至关重要。最近的研究表明，泛素-蛋白酶体途径的蛋白水解在长期突触可塑性中发挥着关键作用。该提案的目标是阐明蛋白酶体的空间和时间作用以及长期突触可塑性中蛋白质合成和降解之间的相互作用。我们将使用高度合适的哺乳动物长期突触可塑性模型系统，即海马中的后期长期增强（L-LTP）。我们的结果表明，蛋白酶体的抑制增强了 L-LTP 的早期翻译依赖性诱导部分，但抑制了 L-LTP 的转录依赖性维持阶段。蛋白酶体介导的 L-LTP 早期部分的增强依赖于 NMDA 受体和 cAMP 依赖性蛋白激酶。我们的数据表明，蛋白酶体抑制通过稳定树突中局部合成的蛋白质来增加 L-LTP 的诱导，但会干扰后期的局部翻译。我们的结果还表明，抑制蛋白酶体会阻断脑源性神经营养因子 (BDNF) 的转录，脑源性神经营养因子是一种 cAMP 反应元件结合蛋白 (CREB) 诱导基因。此外，我们的结果表明，蛋白酶体抑制剂可阻止 ATF4 的降解，ATF4 是一种 CREB ​​阻遏蛋白，已知可抑制 L-LTP 和记忆。因此，蛋白酶体抑制似乎通过阻碍 CREB ​​介导的转录来阻断 L-LTP 的维持。我们的首要目标是研究蛋白酶体抑制增强 L-LTP 诱导的机制，并鉴定由蛋白酶体稳定的新合成蛋白质。在我们的第二个目标下，我们将测试这样的想法：蛋白酶体的阻断会通过导致可塑性负调节因子（例如翻译抑制因子）的积累以及阻碍细胞核中的转录来损害 L-LTP 的维持。利用蛋白质组学、分子生物学和电生理学研究的强大结合，所提出的实验将解决与长期突触可塑性中的蛋白质水解和蛋白质合成之间的关系有关的重要的、尚未解答的问题。公共卫生相关性：当称为突触的神经细胞之间的连接发生变化时，就会形成记忆。最近的发现表明，通过降解调节神经细胞中的蛋白质在记忆中发挥着作用。当蛋白质被称为泛素的小分子标记时，蛋白质会被细胞中称为蛋白酶体的部分降解。在许多大脑疾病和紊乱中，蛋白质降解是异常的。这项研究可以帮助解释脑部疾病引起的记忆丧失和老年发生的记忆丧失。