Molecular mechanisms of structural plasticity of inhibitory GABAergic interneurons

抑制性GABA能中间神经元结构可塑性的分子机制

基本信息

批准号：
10655280
负责人：
Anton Maximov
金额：
$ 64.08万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-13 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655280
关键词：
Ablation Acute Adhesions Affect Animals Architecture Area Basic Science Behavior assessment Binding Sites Bioinformatics Brain Brain Diseases Brain region Cells Data Dendrites Development Distal ERG gene Early identification Future Gene Silencing Genes Genetic Genetic Transcription Glutamates Goals Hippocampus Human Image In Vitro Interneurons Laboratories Learning Longevity Memory Messenger RNA Molecular Morphology Mutant Strains Mice Myoepithelial cell Neurons Outcome Output Parvalbumins Pathway interactions Pattern Perception Performance Pharmaceutical Preparations Physiological Physiology Play Population Property Prosencephalon Publishing Qualifying Regulation Reporter Research RiboTag Ribosomal Proteins Role Sensory Short-Term Memory Signal Transduction Slice Somatostatin Structure Surface Synapses Synaptic Transmission System Testing Transcriptional Activation Whole-Cell Recordings Work cognitive task conditional knockout deep sequencing effective therapy experience experimental study follow-up gene repression hippocampal pyramidal neuron in vivo information processing innovation insight mouse genetics mouse model nervous system disorder neuronal cell body postsynaptic presynaptic programs promoter response screening segregation single cell sequencing spatial memory stem tool transcription factor transcriptome sequencing

项目摘要

Abstract. This proposal aims to investigate the molecular basis of structural plasticity of inhibitory GABAergic interneurons (INs) in the mammalian forebrain. Cortical and hippocampal INs play critical roles in perception and memory storage; their abnormalities have been associated with a broad spectrum of neurological disorders in humans. It is well-established that INs undergo morphological changes and reorganize their networks after sensory experience. This phenomenon appears to be equally important for assembly of synaptic connectivity during development and for processing of information in the brain across lifespan, but the underlying molecular mechanisms are poorly understood. By using unbiased screening and mouse genetics, we have identified transcription factors (TFs) that regulate the architectures of IN networks in the hippocampus. Our preliminary studies support the hypothesis that these TFs are essential for appropriate GABAergic inhibition of pyramidal neurons and memory storage. We will use innovative approaches to elucidate the role of transcription in inhibitory circuits in unique mouse models. Our specific aims are: 1) To test how ablation of TFs in genetically defined IN subtypes impacts their morphologies, wiring and physiology; 2) To examine the consequences of TF signaling on sensory processing and memory formation; and 3) To identify TF effector genes. Taken together, these studies will provide new and significant insights into thus far poorly understood molecular mechanisms of IN plasticity.

抽象的。该提案旨在研究哺乳动物前脑中抑制性 GABA 能中间神经元 (IN) 结构可塑性的分子基础。皮质和海马 IN 在感知和记忆存储中发挥着关键作用；它们的异常与人类广泛的神经系统疾病有关。众所周知，IN 在感官体验后会经历形态变化并重组其网络。这种现象对于发育过程中突触连接的组装以及整个生命周期中大脑中的信息处理似乎同样重要，但人们对潜在的分子机制知之甚少。通过使用公正的筛选和小鼠遗传学，我们已经确定了调节海马 IN 网络结构的转录因子 (TF)。我们的初步研究支持这样的假设：这些 TF 对于锥体神经元和记忆存储的适当 GABA 抑制至关重要。我们将使用创新方法来阐明转录在独特小鼠模型中抑制电路中的作用。我们的具体目标是： 1) 测试基因定义的 IN 亚型中 TF 的消融如何影响其形态、接线和生理学； 2）检查TF信号传导对感觉处理和记忆形成的影响； 3) 鉴定TF效应基因。总而言之，这些研究将为迄今为止人们知之甚少的 IN 可塑性分子机制提供新的、重要的见解。