Transcriptional control of activity-dependent synaptic plasticity

活动依赖性突触可塑性的转录控制

基本信息

批准号：
8527454
负责人：
Richard Cheslock Sando
金额：
$ 2.92万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527454
关键词：
Adult Affect Alleles Animal Model Animals Architecture Base of the Brain Binding Brain Cell Nucleus Chromatin Cognitive Coupling Cytoplasm Development Electrophysiology (science)Excitatory Synapse Exhibits Family Frameshift Mutation Gene Expression Genes Genetic Programming Genetic Techniques Genetic Transcription Glutamates Goals HDAC4 gene Histone Deacetylase Human Impaired cognition In Vitro Laboratories Life Link Mediating Memory Memory Loss Mental Retardation Mental disorders Modeling Modification Molecular Mus Mutation N-Methyl-D-Aspartate Receptors Neurodegenerative Disorders Neurologic Neurons Nuclear Nuclear Import Patients Pharmaceutical Preparations Play Property Proteins Repression Role Sensory Signal Transduction Structure Synapses Synaptic Transmission Synaptic plasticity System Testing Transcription Repressor/Corepressor Transcriptional Regulation abstracting base chemical genetics design experience gain of function in vivo information processing insight member mouse model mutant nervous system disorder neuron development neuronal circuitry neurotransmission optical imaging postnatal programs public health relevance receptor function research study response synaptic function synaptogenesis transcription factor

项目摘要

DESCRIPTION (provided by applicant): Abstract Neurons in the brain can rapidly alter their transcriptional profiles in response to sensory inputs and intrinsic signals. Such experience-dependent changes in expression of genes that build and regulate synapses play a critical role in circuit development and information processing. We hypothesize that HDAC4, a member of the class II histone deacetylase family that shuttles between the nucleus and cytoplasm, controls a transcriptional program essential for synaptic plasticity and spatial memory. This hypothesis is based on the following preliminary results: i) the nuclear import of neuronal HDAC4 and its ability to interact with neuronal chromatin and transcription factors is negatively regulated by NMDA receptors; ii) in the nucleus, HDAC4 represses a restricted group of genes highly enriched in those known to be involved in synaptic function; iii) accumulation of HDAC4 in the nucleus affects both the architecture and strength of excitatory synapses; iv) a frame-shift mutation in the HDAC4 gene has been linked to a rare form of mental retardation in humans; and v) accordingly, mice carrying a truncated form of HDAC4 which mimics the mutant human allele exhibit deficits in neurotransmission and spatial memory. We propose to elucidate the role of HDAC4 in the brain using two unique animal models established in the laboratory. We have developed a new chemical-genetic system that enables drug-inducible control of glutamate release in live and behaving mice. We will take advantage of this system to define the role of synaptic inputs in regulating the localization and transcriptional activity of HDAC4 in vivo. In complementary studies, we will test the hypothesis that memory loss observed of HDAC4-deficient mutants is due to deficits in synaptic plasticity. To attain this goal, we will interrogae synapses of these mice using optical imaging and electrophysiology. We anticipate that these studies will provide important insight to molecular mechanisms of transcriptional control in neurons, and may eventually facilitate the design of new treatments of neurological diseases. !

描述（由申请人提供）：摘要大脑中的神经元可以响应感觉输入和内在信号而快速改变其转录谱。构建和调节突触的基因表达的这种依赖于经验的变化在电路发育和信息处理中发挥着关键作用。我们假设 HDAC4 是 II 类组蛋白脱乙酰酶家族的成员，在细胞核和细胞质之间穿梭，控制着突触可塑性和空间记忆所必需的转录程序。该假设基于以下初步结果： i) 神经元 HDAC4 的核输入及其与神经元染色质和转录因子相互作用的能力受到 NMDA 受体的负调节； ii) 在细胞核中，HDAC4 抑制一组受限制的基因，这些基因在已知参与突触功能的基因中高度富集； iii) HDAC4 在细胞核中的积累影响兴奋性突触的结构和强度； iv) HDAC4 基因中的移码突变与人类一种罕见的智力迟钝有关； v) 因此，携带模拟突变人类等位基因的截短形式的 HDAC4 的小鼠表现出神经传递和空间记忆的缺陷。我们建议使用实验室建立的两种独特的动物模型来阐明 HDAC4 在大脑中的作用。我们开发了一种新的化学遗传系统，可以通过药物诱导控制活体和行为小鼠体内的谷氨酸释放。我们将利用该系统来定义突触输入在调节 HDAC4 体内定位和转录活性中的作用。在补充研究中，我们将检验以下假设：HDAC4 缺陷突变体观察到的记忆丧失是由于突触可塑性缺陷所致。为了实现这一目标，我们将使用光学成像和电生理学来询问这些小鼠的突触。我们预计这些研究将为神经元转录控制的分子机制提供重要的见解，并最终可能促进神经系统疾病新疗法的设计。！