Identifying mechanisms ofsynapse maturation at neuronal subtype resolution

识别神经元亚型分辨率下突触成熟的机制

• 批准号: 10739241
• 负责人: Li Wang
• 金额: $ 9.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739241
• 关键词: ARHGEF5 gene; Acute; Adaptive Behaviors; Affect; Award; Behavior; Biology; Brain; Brain Diseases; Cells; Cerebral cortex; Characteristics; Chemical Synapse; Chromatin; Critical Pathways; DNA Sequence Alteration; Data; Development; Disease; Epigenetic Process; Exhibits; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Genetic study; Genomics; Glutamates; Goals; Heterogeneity; Human; Individual; Interneurons; Knowledge; Label; Learning; Link; Long-Term Effects; Machine Learning; Maintenance; Mediating; Mental disorders; Mentors; Methods; Molecular; Mus; Mutation; Neurons; Pathway interactions; Patients; Phase; Play; Process; Property; Proteins; Proteome; Proteomics; Regulator Genes; Research; Research Project Grants; Resolution; Risk Factors; Rodent Model; Role; Solid; Specificity; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Training; Transcriptional Regulation; autism spectrum disorder; career; cell type; critical period; density; designer receptors exclusively activated by designer drugs; developmental neurobiology; experience; gene regulatory network; in vivo; insight; knock-down; machine learning method; multiple omics; neural circuit; novel; postsynaptic; postsynaptic density protein; programs; protein complex; single-cell RNA sequencing; skills; synaptogenesis; targeted treatment; temporal measurement; tool

Project Summary/Abstract The human brain function relies on the formation and maintenance of precise neural circuits among more than 100 subtypes of neurons. These circuits are mediated by synapses, the characteristics of which vary depending on neuronal subtype. Synaptic dysfunction plays a critical role in most, if not all, human brain disorders. Thus, understanding synaptic diversity and its developmental origin are crucial for us to understand how the brain functions and how it goes awry in mental disorders. During brain development, synapses undergo profound changes to become mature and fully functional. Maturation of glutamatergic synapses involves changes in the postsynaptic density (PSD), a highly sophisticated protein complex composed of >1,000 proteins. However, the compositional changes of the PSD in development were not well characterized. My preliminary data revealed the temporal dynamics of >1,000 PSD proteins during cerebral cortex development, providing initial insight into mechanisms of synapse maturation. Moreover, integrative analysis of the developing PSD proteome and single- cell RNA-seq data suggested that different neuronal subtypes undergo divergent synapse maturation processes. However, we know little about the compositional diversity of neuronal subtype-specific synapses or the different maturation processes they go through. In addition, synapse maturation, diversity, and specificity can be controlled by transcription, but the underlying gene regulatory programs remain elusive. This information is particularly relevant to mental disorders like autism spectrum disorder, in which genetic mutations converge on transcription regulation and synaptic transmission. Thus, the specific aims of this project first seek to uncover the compositional diversity of neuronal subtype-specific synapses in the developing cerebral cortex using a novel chemogenetic method (Aim 1, K99 phase). The second aim is to decode the disease-relevant gene regulatory mechanisms that generate this diversity by applying single-cell genomics and machine learning approaches (Aim 2, K99 phase). Finally, using the training, tools, and preliminary data from the K99 phase of my proposal, I will launch an independent research project that focuses on investigating the effects of neuronal activity on synapse maturation and plasticity at neuronal subtype resolution (R00 phase). Results from these studies will provide insights into synapse diversity, its regulatory mechanisms, and its dysregulation in autism. My long-term goal is to study the functional importance of synapse diversity on neural circuits and behaviors and develop targeted therapies to alleviate synaptic dysfunction in mental disorders in patients. Additional training obtained during this award in developmental neurobiology (with Dr. Arnold Kriegstein), synaptic biology (with Dr. Robert Edwards), chemogenetics (with Dr. Alice Ting), and advanced machine learning (with Dr. Jingjing Li), combined with my previous experience in rodent models, proteomics, and single-cell genomics will provide me with a solid foundation for an independent research career to achieve my goal.

项目摘要/摘要 人脑功能依赖于超过的精确神经回路的形成和维护 100个神经元的亚型。这些电路是由突触介导的，其特征的特征因 在神经元亚型上。突触功能障碍在大多数（如果不是全部）人脑疾病中起关键作用。因此， 了解突触多样性及其发育起源对我们了解大脑如何 功能及其在精神障碍方面的出现方式。在大脑发育过程中，突触会经历深刻的 变化变得成熟和功能齐全。谷氨酸能突触的成熟涉及变化 突触后密度（PSD），一种高度复杂的蛋白质复合物，由> 1,000个蛋白质组成。但是， PSD在开发中的组成变化没有很好地表征。我的初步数据显示 大脑皮质发育过程中> 1,000 psd蛋白的时间动力学 突触成熟的机制。此外，对正在发展的PSD蛋白质组和单一的综合分析 细胞RNA-seq数据表明，不同的神经元亚型经历了突触成熟过程。 但是，我们对神经元亚型特异性突触的组成多样性或不同 他们经历的成熟过程。此外，突触成熟，多样性和特异性可以是 通过转录控制，但基本的基因调节程序仍然难以捉摸。此信息是 与自闭症谱系障碍之类的精神障碍特别相关，其中遗传突变会融合 转录调节和突触传播。因此，该项目的具体目的首先寻求揭露 使用新颖的大脑皮层中神经元亚型特异性突触的组成多样性 化学发生方法（AIM 1，K99期）。第二个目的是解码与疾病相关的基因调节 通过应用单细胞基因组学和机器学习方法来产生这种多样性的机制（目标 2，K99阶段）。最后，使用我提案的K99阶段的培训，工具和初步数据，我将 启动一个独立的研究项目，侧重于研究神经元活动对突触的影响 神经元亚型分辨率（R00相）的成熟和可塑性。这些研究的结果将提供 对突触多样性，其调节机制及其自闭症失调的见解。我的长期目标是 研究突触多样性对神经回路和行为的功能重要性，并发展有针对性的 减轻患者精神障碍突触功能障碍的疗法。在此期间获得的其他培训 发育神经生物学奖（与Arnold Kriegstein博士），突触生物学（与Robert Edwards博士）， 化学遗传学（与Alice博士）和高级机器学习（与Jingjing Li博士一起），与我的 以前在啮齿动物模型，蛋白质组学和单细胞基因组学方面的经验将为我提供固体 独立研究职业的基础，以实现我的目标。