Local mRNA degradation in GluR1 signaling, synaptic plasticity, and cognitive function

GluR1 信号传导、突触可塑性和认知功能中的局部 mRNA 降解

• 批准号: 10055968
• 负责人: Dilek Colak
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-06 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055968
• 关键词: APC2 gene; Address; Adult; Axon; Behavioral Assay; Brain; Coupled; Defect; Degradation Pathway; Dendrites; Dendritic Spines; Development; Disease; Electrophysiology (science); Endocytosis; Event; Foundations; Functional disorder; Genetic; Genetic Translation; Glutamate Receptor; Goals; Growth Cones; Hippocampus (Brain); Human; In Vitro; Knockout Mice; Learning; Link; Literature; Measures; Mediating; Memory; Messenger RNA; Microfluidic Microchips; Modeling; Molecular; Mus; Mutant Strains Mice; Neurocognitive; Neurodevelopmental Disorder; Neurons; Pathway interactions; Physiological; Play; Process; Protein Biosynthesis; Proteins; Proteolysis; Proteome; Publishing; RNA; Regulation; Regulatory Pathway; Research; Research Proposals; Role; Schizophrenia; Signal Transduction; Site; Slice; Small Interfering RNA; Structure; Surface; Synapses; Synaptic plasticity; Techniques; Testing; Time; Tissues; Translational Derepression; Translational Repression; Translations; Vertebral column; Work; autism spectrum disorder; axon growth; axon guidance; base; behavior test; cognitive function; cognitive performance; density; design; excitatory neuron; experience; experimental study; insight; mRNA Decay; mRNA Stability; mRNA Transcript Degradation; mouse model; neurocognitive disorder; neuropsychiatric disorder; novel; receptor; receptor expression; synaptic function; transcriptome sequencing

PROJECT SUMMARY A major regulator of synaptic function is local protein synthesis. Deep RNA sequencing has revealed that there are thousands of dendritically localized mRNAs. Local translation of selected mRNAs in dendrites provides a fast, adaptive mechanism for the experience-dependent formation of new synapses or the stability of pre- existing connections. This plasticity underlies changes in neuronal network dynamics and is therefore thought to be the foundation of learning and memory. Altered protein synthesis and synaptic plasticity are associated with a variety of neurodevelopmental disorders. However, the pathways that regulate the dendritic proteome are not well understood. Protein synthesis in dendrites requires precise regulation of local mRNA stability and translation. A great amount of prior research has addressed the pathways that regulate translational derepression in dendrites. However, the mechanisms that control mRNA levels during synaptic function have not been demonstrated. We have recently shown that intra-axonal translation coupled to the mRNA-degradation pathway `Nonsense Mediated mRNA Decay' (NMD) controls a switch in receptor expression and thereby regulates axon guidance; indicating that mRNA turnover is a key player in local protein synthesis. Currently, it is not known whether mRNA stability in dendrites contribute to the regulation of synaptic plasticity. The goal of this application is to understand the contribution of intra-dendritic translation coupled to mRNA- degradation pathway NMD to synaptic plasticity and cognitive performance. The synaptic plasticity protein Arc is a known target of NMD-mediated mRNA degradation, serving to limit the amount of Arc in dendrites. We have found that, in addition to Arc, NMD limits the amount of various other proteins involved in GluR1 regulation, which is essential for modulation of synaptic strength. Based on the published literature and our preliminary studies, we hypothesize that local NMD is as essential for synaptic function as it is for axon guidance. To test this hypothesis, we propose to determine whether NMD: 1) locally functions in dendrites; 2) promotes synaptic strength by restricting either internalization or translational repression of GluR1; 3) plays a role in different forms of synaptic plasticity (e.g. LTP and LTD); 4) is required for learning and memory. We will use a combination of techniques including a novel microfluidic device to uniquely study synaptic events, an inducible-genetic mouse model, electrophysiology and behavioral assays. Although NMD is the only RNA regulatory pathway linked to numerous neurocognitive disorders, it represents a relatively unexplored mechanism for regulating synaptic function. The successful completion of this research will provide a coherent view of local proteome dynamics in synaptic plasticity and might be valuable for providing new insights into the mechanisms of synaptic dysfunction and neurocognitive diseases.

项目摘要 突触功能的主要调节剂是局部蛋白质合成。深度RNA测序揭示了那里 是成千上万的树枝状局部mRNA。树突中选定的mRNA的本地翻译提供了 快速，适应性机制，用于经验依赖新突触的形成或预先的稳定性 现有连接。这种可塑性是神经元网络动态变化的基础，因此被认为 成为学习和记忆的基础。蛋白质合成和突触可塑性的改变是相关的 患有各种神经发育障碍。但是，调节树突状蛋白质组的途径 不太了解。 树突中的蛋白质合成需要精确调节局部mRNA稳定性和翻译。很棒 先前的研究数量已经解决了调节树突中翻译消除的途径。 但是，尚未证明控制突触功能过程中mRNA水平的机制。我们 最近表明，轴内翻译与mRNA降解途径耦合 介导的mRNA衰变'（NMD）控制受体表达的开关，从而调节轴突的指导； 表明mRNA转换是局部蛋白质合成的关键参与者。目前，尚不知道是否 树突中的mRNA稳定性有助于调节突触可塑性。 该应用的目的是了解树突内翻译与mRNA-的贡献 降解途径NMD可突触可塑性和认知性能。突触可塑性蛋白弧 是NMD介导的mRNA降解的已知靶标，可限制树突中的弧量。我们 已经发现，除了ARC外，NMD还限制了参与GLUR1的其他各种蛋白质的量 调节，这对于调节突触强度至关重要。根据已发表的文献和我们的 初步研究，我们假设局部NMD对于突触功能至关重要 指导。为了检验这一假设，我们建议确定NMD是否：1）局部在树突中的功能； 2） 通过限制GLUR1的内在化或翻译抑制来促进突触强度； 3）扮演a 在不同形式的突触可塑性（例如LTP和LTD）中的作用； 4）学习和记忆是必需的。我们将 使用包括新型微流体装置在内的技术组合来独特研究突触事件， 诱导遗传小鼠模型，电生理学和行为测定。虽然NMD是唯一的RNA 与众多神经认知障碍相关的调节途径，它代表了一个相对尚未探索的 调节突触功能的机制。这项研究的成功完成将提供连贯的 突触可塑性中局部蛋白质组动态的视图，对于提供新的见解可能是有价值的 突触功能障碍和神经认知疾病的机制。