Dynamic control of synapse organization and function by cleft-resident molecules

裂隙驻留分子对突触组织和功能的动态控制

• 批准号: 10320978
• 负责人: Thomas Biederer
• 金额: $ 54.22万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320978
• 关键词: Acute; Adhesions; Adhesives; Adopted; Architecture; Area; Biological; Biological Assay; Brain; Brain Diseases; Cell Adhesion Molecules; Cells; Cellular Assay; Chronic; Complex; Data; Data Set; Development; Disease; Engineering; Excitatory Synapse; Financial compensation; Image; Individual; Knock-out; Label; Learning; Link; Location; Maps; Measures; Molecular; Monitor; Mutation; Neurodevelopmental Disorder; Neurons; Pattern; Peptide Hydrolases; Physiological; Positioning Attribute; Property; Proteins; Proteome; Public Health; Publishing; Reporter; Research; Role; Schizophrenia; Shapes; Side; Signal Transduction; Site; Structure; Structure-Activity Relationship; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic plasticity; System; Testing; autism spectrum disorder; density; experience; extracellular; functional plasticity; insight; interest; knock-down; link protein; loss of function; nanoscale; nervous system disorder; novel; overexpression; postsynaptic; programs; protein complex; receptor; response; synaptic function; synaptogenesis; tool

The synaptic cleft is a conserved and integral component of central synapses. It is comprised of protein complexes that span across it, and their adhesive interactions and signaling roles guide synapse development. Their relevance is underscored by the mutations in synapse-organizing proteins that are linked to complex brain disorders including autism-spectrum disorders and schizophrenia. Yet, the molecular patterning and dynamics of synaptic cleft components remain largely unknown. This contrasts with our understanding of the nanoscale organization of pre- and post-synaptic compartments, which is elucidating our understanding of synaptic structure and function. Moreover, acute synapse-organizing roles of cleft proteins at mature synapses and the functional interplay of trans-synaptic interaction systems remain to be defined. Our central hypothesis is that the properties and plasticity of mature synapses are dynamically instructed by select cleft components. This proposal builds on preliminary and previously published results by the collaborating groups that synaptic adhesion complexes are differentially localized within the cleft, shape this compartment, can undergo rapid changes in synaptic abundance upon plasticity induction, and alter long-term synaptic plasticity. Three specific aims will be pursued to test our hypothesis. First, we will test roles of trans-synaptic interactions in acutely instructing pre- and postsynaptic function. Second, it is our aim to determine the molecular and organizational dynamics of the cleft during long-term plasticity. Third, we will identify cleft proteins that guide changes during plasticity. Our approaches include tools to acutely perturb trans-synaptic interactions, proximity labeling to identify cleft-resident molecules and monitor them during plasticity, superresolution imaging to map their cleft locations, and cell biological and physiological functional assays. We anticipate to determine the molecular patterning and dynamics of the synaptic cleft and to identify how trans-synaptic interactions actively shape synaptic function. This expected progress is significant because it will define the cleft as a molecularly organized and acutely controlled cellular compartment that instructs synaptic properties. Moreover, this research can determine how a dynamic remodeling of the cleft architecture underlies the activity-dependent plastic changes at synapses. Synaptic organization and function are disrupted in neurodevelopmental and neurological disorders, and this program will provide information for defining how these diseases impact the cleft and may even originate in it to alter synaptic properties.

突触间隙是中央突触的保守组成部分。它由蛋白质组成 跨越它的复合体及其粘附相互作用和信号传导作用指导突触的发育。 与复杂的突触组织蛋白相关的突变强调了它们的相关性。 脑部疾病，包括自闭症谱系障碍和精神分裂症。然而，分子图案和 突触间隙成分的动力学仍然很大程度上未知。这与我们的理解形成鲜明对比 突触前和突触后区室的纳米级组织，这阐明了我们对 突触结构和功能。此外，成熟突触中裂口蛋白的急性突触组织作用 跨突触相互作用系统的功能相互作用仍有待定义。我们的中心假设 成熟突触的特性和可塑性是由选择的裂隙成分动态指示的。 该提案建立在突触合作小组先前发布的初步结果的基础上 粘附复合物在裂隙内有不同的定位，塑造该隔室，可以快速经历 可塑性诱导时突触丰度的变化，并改变长期突触可塑性。三具体 我们将追求目标来检验我们的假设。首先，我们将测试跨突触相互作用在急性中的作用 指示突触前和突触后功能。其次，我们的目标是确定分子和组织 长期塑性过程中裂缝的动力学。第三，我们将鉴定在过程中指导变化的裂解蛋白。 可塑性。我们的方法包括剧烈扰乱跨突触相互作用的工具、邻近标记 识别裂隙驻留​​分子并在可塑性、超分辨率成像过程中对其进行监测以绘制其裂隙图 位置以及细胞生物学和生理功能测定。我们期望确定分子 突触间隙的模式和动态，并确定跨突触相互作用如何主动塑造 突触功能。这一预期进展意义重大，因为它将把裂隙定义为分子 有组织且受到严格控制的细胞区室，指示突触特性。而且，这 研究可以确定裂隙结构的动态重塑如何成为活动依赖性的基础 突触的可塑性变化。突触组织和功能在神经发育和发育过程中受到破坏 神经系统疾病，该计划将提供信息来定义这些疾病如何影响 裂，甚至可能起源于它来改变突触特性。