Molecular basis of glutamatergic synapse function in inhibitory interneurons

抑制性中间神经元谷氨酸能突触功能的分子基础

• 批准号: 10684839
• 负责人: Alexei Mansfield Bygrave
• 金额: $ 24.47万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684839
• 关键词: Ankyrin Repeat; Area; Basic Science; Behavior; Binding Proteins; Biochemical; Biology; Brain; Cell physiology; Complex; Coupled; DLG4 gene; Data; Data Set; Dendritic Spines; Diffusion; Dimensions; Disease; Electrophysiology (science); Functional disorder; Glutamates; Goals; Health; Hippocampus; Imaging Techniques; Interneurons; Investigation; Knock-out; Knowledge; Link; Liquid substance; Mass Spectrum Analysis; Mental disorders; Mentors; Mission; Molecular; Neurons; Outcome; Parvalbumins; Phase; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiology; Positioning Attribute; Process; Property; Proteins; Public Health; Regulation; Research; Shapes; Signal Transduction; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic Intervention; Training; United States National Institutes of Health; career; career development; cell type; excitatory neuron; expectation; improved; innovation; insight; nervous system disorder; neural circuit; novel; novel therapeutic intervention; overexpression; risk variant; scaffold; skills; synaptic function; targeted treatment; tenure track

PROJECT SUMMARY Dysfunction of glutamatergic synapses in inhibitory interneurons (INs) is increasingly being linked to psychiatric diseases and neurological disorders. However, our understanding of the molecular mechanisms distinguishing glutamatergic synapse function in INs from those in excitatory neurons is hindered by a lack of insight into their molecular composition. The applicant's long-term goal is to develop an independent research career focusing on the molecular basis of glutamatergic synapse function in INs. The overall objective of this proposal is to identify IN-specific excitatory synaptic proteins (IN-ExSPs), and assess how these proteins regulate glutamatergic synapse function in INs. This proposal is aligned with the central hypothesis that unique protein specializations support the function of glutamatergic synapses in INs, at least in part, through the process of liquid-liquid phase separation (LLPS), a phenomenon that it ubiquitous across biology and has been recently linked to glutamatergic synapse function. The project's rationale is to establish a molecular framework for understanding how IN glutamatergic synapses impact health and disease. The central hypothesis will be tested by pursuing two specific aims: 1) Identify glutamatergic synaptic proteins specific to or enriched in interneurons; and 2) Evaluate the contribution of IN-ExSPs to glutamatergic synapse function in interneurons. Under the first aim, cell-type-specific immunoisolation and mass spectrometry will be used to identify novel IN-ExSPs. For the second aim, IN-ExSPs will be screened for LLPS-properties, and the effect of their overexpression or knockout on IN glutamatergic synapse function, and behaviour, will be assessed. The proposed research is innovative, in the applicant's opinion, firstly because it introduces a cell-type-specific dimension to the molecular-investigation of glutamatergic synapses; and secondly, because it assesses how IN-ExSPs that undergo LLPS influence glutamatergic synapse function in INs, which largely lack dendritic spines and therefore have a unique problem to overcome in terms of biochemical compartmentalization and synapse stability. The proposed research is significant because it will yield new insights into the molecular mechanisms supporting the function of glutamatergic synapses in INs, an area in which very little is currently known. This could uncover innovative strategies to selectively increase the function of glutamatergic synapses in INs, providing more precise therapeutic interventions to tackle psychiatric diseases and neurological disorders. The applicant has assembled an expert mentoring team to provide the technical training and career development guidance required to obtain a tenure track academic position. In particular, the applicant will receive training in electrophysiology and analysis of quantitative mass spectrometry data, and will further develop skills in molecular, biochemical, and advanced imaging techniques.

项目概要 抑制性中间神经元 (IN) 谷氨酸突触功能障碍越来越多地与精神疾病相关 疾病和神经系统疾病。然而，我们对分子机制的理解区分 兴奋性神经元中的 IN 中的谷氨酸突触功能由于缺乏对其的了解而受到阻碍 分子组成。申请人的长期目标是发展独立的研究生涯，重点关注 基于 IN 中谷氨酸突触功能的分子基础。该提案的总体目标是 识别 IN 特异性兴奋性突触蛋白 (IN-ExSP)，并评估这些蛋白如何调节 IN 中的谷氨酸突触功能。该提议与中心假设一致，即独特的蛋白质 专业化支持 IN 中谷氨酸突触的功能，至少部分是通过以下过程： 液-液相分离（LLPS），这种现象在生物学中普遍存在，并且最近被 与谷氨酸能突触功能有关。该项目的基本原理是建立一个分子框架 了解 IN 谷氨酸突触如何影响健康和疾病。中心假设将被检验 通过追求两个具体目标：1）识别中间神经元特有或富集的谷氨酸突触蛋白； 2) 评估 IN-ExSP 对中间神经元谷氨酸突触功能的贡献。在第一个下 目的，细胞类型特异性免疫分离和质谱分析将用于鉴定新型 IN-ExSP。对于 第二个目标是筛选 IN-ExSP 的 LLPS 特性及其过表达或敲除的影响 将评估 IN 谷氨酸突触功能和行为。所提出的研究具有创新性， 申请人的意见，首先是因为它在分子研究中引入了细胞类型特异性的维度 谷氨酸能突触；其次，因为它评估了经历 LLPS 的 IN-ExSP 如何影响 IN 中的谷氨酸突触功能，很大程度上缺乏树突棘，因此有一个独特的问题 克服生化区划和突触稳定性方面的问题。拟议的研究是 意义重大，因为它将对支持功能的分子机制产生新的见解 IN 中的谷氨酸突触，目前对此领域知之甚少。这可能会发现创新 选择性增加 IN 中谷氨酸突触功能的策略，提供更精确的 解决精神疾病和神经系统疾病的治疗干预措施。申请人已集合 专家指导团队提供获得所需的技术培训和职业发展指导 终身教职学术职位。特别是，申请人将接受电生理学和分析方面的培训 定量质谱数据，并将进一步发展分子、生物化学和先进的技能 成像技术。