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: 10540417
• 负责人: Thomas Biederer
• 金额: $ 53.22万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540417
• 关键词: Acute; Adhesions; Adhesives; Adopted; Architecture; Area; Biological; Biological Assay; Brain; Brain Diseases; Cell Adhesion Molecules; Cell Communication; Cells; Cellular Assay; Chronic; Collaborations; Compensation; Complex; Data; Data Set; Development; Disease; Engineering; Excitatory Synapse; Image; Individual; Knock-out; Label; Learning; Link; Location; Maps; Measures; Molecular; Monitor; Mutation; Neurodevelopmental Disorder; Neurons; Pattern; Peptide Hydrolases; Physiological; Positioning Attribute; Property; Protein Dynamics; 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; presynaptic; programs; protein complex; receptor; response; superresolution imaging; 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.

突触裂缝是中央突触的保守和组成部分。它由蛋白质组成 跨越它的复合物以及它们的粘合剂相互作用和信号传导作用指导突触的发展。 它们的相关性是由突触 - 组织蛋白的突变强调的，这些蛋白与复合物有关 脑部疾病，包括自闭症谱系疾病和精神分裂症。然而，分子图案和 突触裂缝成分的动力学在很大程度上未知。这与我们对 纳米级组织前后突触室的组织，这阐明了我们对 突触结构和功能。此外，急性突触组织在成熟突触中的裂口蛋白的作用 反式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 是通过精选的裂口组件动态指导成熟突触的特性和可塑性。 该提案建立在触发的协作小组的初步和先前发表的结果上 粘附复合物在裂缝内差异化，塑造该隔室，可以快速经历 突触诱导时突触丰度的变化，并改变长期突触可塑性。三个具体 将追求目标以检验我们的假设。首先，我们将测试反反突触相互作用在急性中的作用 指导前后突触后功能。其次，我们的目的是确定分子和组织 长期可塑性期间裂缝的动力学。第三，我们将确定指导在期间引导变化的裂缝蛋白 可塑性。我们的方法包括急性扰动反式突触相互作用的工具，接近标记 识别居住的分子并在可塑性期间监视它们，并将上分辨率成像绘制left 位置以及细胞生物学和生理功能测定。我们预计将确定分子 突触裂缝的图案和动力学，并确定跨突触的相互作用如何主动塑造 突触功能。这种预期的进展很大，因为它将将裂缝定义为分子 有组织的，急性控制的细胞室，指示突触性质。而且，这 研究可以确定裂缝结构的动态重塑如何依赖于活动 突触时的塑料变化。突触组织和功能在神经发育和 神经系统疾病，该计划将提供信息，以定义这些疾病如何影响 裂缝，甚至可能起源于它来改变突触性质。