Nanoscale organization of the inhibitory synapse during synaptic plasticity

突触可塑性过程中抑制性突触的纳米级组织

• 批准号: 9885556
• 负责人: Katharine Rachel Smith
• 金额: $ 38.37万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885556
• 关键词: 3-Dimensional; AMPA Receptors; Acute; Animals; Architecture; Behavior; Brain; Brain Diseases; Cell Adhesion Molecules; Cognition; Computer Models; Data; Disease; Disease model; Electrophysiology (science); Equilibrium; Future; Glutamates; Goals; Growth; Imaging Techniques; Impairment; Inhibitory Synapse; Interneurons; Laboratories; Learning; Lighting; Location; Mediating; Memory; Microscopy; Modernization; Molecular; Neuraxis; Neurologic; Neurons; Output; Pathology; Phosphorylation; Play; Positioning Attribute; Regulation; Resolution; Role; Schizophrenia; Site; Slice; Stroke; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Time; Work; autism spectrum disorder; functional outcomes; gephyrin; information processing; nanoscale; nervous system disorder; neuroligin 2; neuronal circuitry; neuronal excitability; neurotransmitter release; novel; novel therapeutic intervention; palmitoylation; postsynaptic; postsynaptic density protein; presynaptic; receptor; scaffold; synaptic function; synaptic inhibition; three dimensional structure

The correct balance between excitation and inhibition (E/I balance) in neuronal circuits is essential for learning and memory, cognition and behavior. Disrupted inhibition leading to elevated neuronal and circuit excitability is thought to underlie the pathology of numerous neurological disorders, therefore a comprehensive understanding of the molecular mechanisms involved in synaptic inhibition will have the potential to direct new therapeutic strategies for treating these conditions. GABAergic inhibitory synapses mediate the majority of synaptic inhibition in the central nervous system, and their plasticity controls neuronal excitability and function. The number of GABAA receptors (GABAARs) at inhibitory postsynaptic sites is a key determinant of inhibitory synapse strength and hence neuronal inhibition. Therefore defining mechanisms by which synaptic GABAARs are clustered and how they are altered in synaptic plasticity is imperative for understanding inhibition and its disruption in brain disorders. Using the versatile super-resolution imaging technique, Structured Illumination Microscopy (SIM), we find that GABAARs and their scaffold, gephyrin, form nanoscale subsynaptic domains (SSDs) in the inhibitory postsynaptic domain, are modulated during plasticity, and form closely associated pairs with presynaptic release SSDs in the active zone, suggesting that a modular nanoscale architecture for the inhibitory synapse may be important for their plasticity and function. Our goal is to determine the mechanisms that control inhibitory nanoscale organization, understand how this organization influences inhibitory synaptic function and is altered during synaptic plasticity, and determine how these facets differ between diverse inhibitory synapse subtypes. This proposal will (1) determine the mechanisms underlying the formation of postsynaptic inhibitory SSDs during activity-dependent synapse growth, (2) define the mechanisms and functional relevance of postsynaptic SSD clustering opposite presynaptic release sites, and (3) examine how subcellular location and interneuron input influence inhibitory nanoscale organization. These aims will test our overarching hypothesis that inhibitory synaptic nanoscale organization underlies inhibitory synaptic strength, and its dynamic regulation is a crucial mechanism for synaptic plasticity. These proposed studies will be significant, being the first comprehensive mechanistic and functional examination of inhibitory synapse architecture at nanoscale resolution (in both culture and slice) and in real-time during short- and long-term plasticity paradigms. The widespread importance of this work is that it will greatly expand our understanding of the detailed mechanisms that control inhibitory synaptic plasticity and inhibition, which is critical for maintaining E/I balance and neuronal function. Moreover, determining the nanoscale structure of inhibitory synapses in healthy brains will pave the way for future studies in disease models to provide novel understanding of how inhibitory synapse structure, function and E/I balance are disrupted in neuropathological disorders.

神经元回路中兴奋和抑制之间的正确平衡（E/I平衡）对学习至关重要 以及记忆、认知和行为。中断抑制导致神经元和回路兴奋性升高， 被认为是许多神经系统疾病的病理基础，因此， 了解突触抑制的分子机制将有可能指导新的 治疗这些病症的治疗策略。GABA能抑制性突触介导大多数 中枢神经系统中的突触抑制，以及它们的可塑性控制神经元的兴奋性和功能。 抑制性突触后位点的GABAA受体（GABAAR）的数量是抑制性突触后位点的关键决定因素。 突触强度和因此神经元抑制。因此定义了突触GABAAR 聚集在一起，它们在突触可塑性中是如何改变的，这对于理解抑制及其 大脑紊乱的破坏。利用多功能的超分辨率成像技术，结构照明 在SIM显微镜下，我们发现GABAARs和它们的支架，桥蛋白，形成纳米级的突触下结构域， 在可塑性过程中，抑制性突触后结构域中的SSD被调节，并形成密切相关的对 与突触前释放固态硬盘在活动区，这表明，一个模块化的纳米级架构， 抑制性突触可能对其可塑性和功能很重要。我们的目标是确定 控制抑制性纳米结构，了解这种结构如何影响抑制性突触 功能，并在突触可塑性过程中改变，并确定这些方面如何在不同的 抑制性突触亚型。这一建议将（1）确定形成的机制， 活动依赖性突触生长过程中突触后抑制性SSD，（2）定义机制， 突触后SSD的功能相关性聚集在突触前释放位点的对面，以及（3）研究如何 亚细胞定位和中间神经元输入影响抑制性纳米级组织。这些目标将考验我们的 抑制性突触纳米级组织是抑制性突触强度的基础， 它的动态调节是突触可塑性的重要机制。这些拟议的研究将 这是第一次对抑制性突触进行全面的机制和功能检查， 纳米级分辨率（培养物和切片）以及短期和长期实时架构 可塑性范例这项工作的广泛重要性在于，它将大大扩展我们对 控制抑制性突触可塑性和抑制的详细机制，这对于维持 E/I平衡和神经元功能。此外，确定抑制性突触的纳米级结构， 健康的大脑将为未来的疾病模型研究铺平道路， 抑制性突触结构、功能和E/I平衡在神经病理学病症中被破坏。