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.

项目总结 突触功能的一个主要调节因素是局部蛋白质合成。深度RNA测序显示，在那里 是数以千计的树突定位的mRNAs。树突中选定的mRNAs的本地翻译提供了 新突触的形成或前突触的稳定性的快速适应机制 现有连接。这种可塑性是神经元网络动力学变化的基础，因此被认为 成为学习和记忆的基础。蛋白质合成改变与突触可塑性有关 患有各种神经发育障碍。然而，调节树突状蛋白质组的途径 都没有被很好地理解。 树突状细胞中的蛋白质合成需要对局部mRNA的稳定性和翻译进行精确的调控。一位伟大的 大量先前的研究已经解决了调节树突中翻译去阻遏的途径。 然而，在突触功能过程中控制mRNA水平的机制还没有被证实。我们 最近发现，轴突内翻译与信使核糖核酸降解途径相关联是胡说八道。 介导的信使核糖核酸衰变(NMD)控制受体表达的开关，从而调节轴突引导； 说明信使核糖核酸的周转是局部蛋白质合成的关键。目前尚不清楚， 树突状细胞中mRNA的稳定性有助于突触可塑性的调节。 这个应用程序的目标是了解树突内翻译对mRNA的贡献。 降解途径NMD对突触可塑性和认知能力的影响。突触可塑性蛋白Arc 是NMD介导的mRNA降解的已知靶点，用于限制树突中Arc的数量。我们 已经发现，除了Arc，NMD还限制了GluR1中涉及的各种其他蛋白质的数量 调节，这是调节突触强度所必需的。基于已发表的文献和我们的 初步研究，我们假设局部NMD对突触功能和轴突一样重要 指导。为了验证这一假设，我们建议确定NMD：1)在树突中起局部作用；2) 通过限制GluR1的内化或翻译抑制来促进突触强度；3)发挥 在不同形式的突触可塑性中发挥作用(如LTP和LTD)；4)学习和记忆需要。我们会 使用包括新型微流控设备在内的多种技术组合来独特地研究突触事件，以及 可诱导遗传小鼠模型、电生理学和行为学检测。尽管NMD是唯一的RNA 调节通路与众多神经认知障碍有关，它代表着一种相对未被探索的 调节突触功能的机制。这项研究的成功完成将提供一个连贯的 突触可塑性中局部蛋白质组动力学的观点，可能对提供对突触可塑性的新的见解有价值 突触功能障碍和神经认知疾病的机制。