The role of synaptonuclear signaling proteins in long-term hippocampal synaptic plasticity

突触核信号蛋白在长期海马突触可塑性中的作用

• 批准号: 9327211
• 负责人: Wendy Herbst
• 金额: $ 3.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2020-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327211
• 关键词: Acute; Address; Adult; Alzheimer' s Disease; Back; Binding; Binding Proteins; Biochemical; Biological; Biological Assay; Brain; CREB1 gene; Calcium Signaling; Cell Nucleus; Co-Immunoprecipitations; Communication; Complement; Complex; Data; Disease; Electrophysiology (science); Enzymes; Event; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glutamate Receptor; Hippocampus (Brain); Histones; Human; Importins; Investigation; Knock-out; Knockout Mice; Knowledge; Long-Term Depression; Long-Term Potentiation; Mass Spectrum Analysis; Memory; Mus; Nervous System Physiology; Nervous system structure; Neurobiology; Neurologic Dysfunctions; Neuronal Plasticity; Neurons; Nuclear; Nuclear Import; Nuclear Localization Signal; Phase; Phosphotransferases; Population; Process; Proteins; Receptor Activation; Recruitment Activity; Regulator Genes; Research; Resources; Rest; Role; Schizophrenia; Sensory; Signal Transduction; Signaling Molecule; Signaling Protein; Slice; Stimulus; Synapses; Synaptic plasticity; Synaptosomes; Testing; Transcription Coactivator; Travel; Work; addiction; alpha Karyopherins; experience; experimental study; insight; nervous system disorder; neurodevelopment; neuropsychiatric disorder; novel; nucleocytoplasmic transport; programs; protein function; response; retrograde transport; transcription factor; transcriptome; transcriptome sequencing

Project Abstract: Synaptic plasticity is a fundamental principle of the nervous system and underlies many neurobiological processes including neurodevelopment, sensory processing, and memory storage. New gene transcription is required for long-lasting plasticity, and this requirement for transcription indicates that signals from stimulated synapses must reach the nucleus via synaptonuclear signaling. One such mechanism of synaptonuclear signaling that is essential for long-term plasticity is the physical translocation of signaling proteins from the synapse to the nucleus. While a few dozen proteins are known to undergo activity- dependent synapse-to-nucleus translocation, little work has been done to systematically identify the population of proteins that undergo this translocation. Moreover, little is known about the gene expression programs that these synaptonuclear signaling proteins initiate. This project aims to: 1) Characterize the gene regulatory role of an exemplar synaptonuclear signaling protein, CREB-Regulated Transcriptional Coactivator 1 (CRTC1); and 2) Systematically identify proteins that undergo synapse-to-nucleus translocation during plasticity. For the first aim, electrophysiology will be used to characterize late-phase long-term potentiation (LTP) and long-term depression (LTD) in acute hippocampal slices from CRTC1 conditional knockout mice to study the function of CRTC1 in long-lasting plasticity. These studies will be complemented with RNA sequencing to determine the role of CRTC1 in the transcriptional programs that give rise to long-term plasticity. In the second aim, novel synaptonuclear signaling proteins will be identified using a biochemical screen. In brief, mass spectrometry will be used to identify synaptic proteins that are bound to the importin β1 nuclear transport complex and are therefore likely to be cargo destined for nuclear import. Candidate proteins will be studied in the context of synaptic plasticity. Identifying novel proteins that translocate from synapse to nucleus will provide insight into the types of signals that translocate during plasticity, and the identity and function of these synaptonuclear signaling proteins will provide insights into the regulation of gene expression during plasticity. Synaptic plasticity is widely involved in neurological function and dysfunction, and therefore addressing these fundamental questions about synaptic plasticity will provide insight into the mechanisms underlying many neurological and neuropsychiatric disorders.

项目摘要： 突触可塑性是神经系统的基本原理，是许多神经生物学的基础。 包括神经发育、感觉处理和记忆存储的过程。新基因转录 是持久可塑性所必需的，而这种转录要求表明，来自 受刺激的突触必须通过突触核信号到达细胞核。一种这样的机制是 突触核信号对长期可塑性至关重要，它是信号的物理转移 从突触到细胞核的蛋白质。虽然已知有几十种蛋白质具有活性- 依赖的突触到细胞核的易位，几乎没有做过系统地识别 经历这种易位的蛋白质群体。此外，人们对这种基因的表达知之甚少。 这些突触核信号蛋白启动的程序。本项目的目标是：1)描述 典型突触核信号蛋白CREB调节转录的基因调控作用 共激活因子1(CRTC1)；和2)系统地识别经历突触到核的蛋白质 可塑性过程中的移位。对于第一个目标，将使用电生理学来表征晚期 CRTC1急性海马片的长时程增强(LTP)和长时程增强(LTD) 条件性基因敲除小鼠研究CRTC1在长期可塑性中的作用。这些研究将是 与RNA测序互补，以确定CRTC1在转录程序中的作用 会产生长期的可塑性。第二个目标是鉴定新的突触核信号蛋白。 使用生化筛查。简而言之，质谱学将被用来识别 运往Importinβ1核运输综合体，因此很可能是运往核运输的货物 导入。候选蛋白质将在突触可塑性的背景下进行研究。鉴定新的蛋白质， 从突触到核团的转移将提供对在以下过程中转移的信号类型的洞察 可塑性，以及这些突触核信号蛋白的身份和功能将为深入了解 可塑性过程中基因表达的调控。突触可塑性广泛参与神经学研究 功能和功能障碍，因此解决了这些关于突触可塑性的基本问题 将提供对许多神经和神经精神障碍潜在机制的洞察。