Molecular mechanisms of target-specific synapse formation

靶标特异性突触形成的分子机制

• 批准号: 10184919
• 负责人: Megan Elise Williams
• 金额: $ 54.94万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10184919
• 关键词: Adult; Alternative Splicing; Amino Acids; Axon; Binding; Biological Assay; Brain; Brain Diseases; Cell Adhesion Molecules; Cognitive; Complex; Data; Defect; Dendrites; Development; Disease; Electrophysiology (science); Etiology; Exons; Filopodia; Genes; Glutamates; Goals; Hippocampus (Brain); Human; Impairment; Intellectual functioning disability; Knockout Mice; Knowledge; Learning; Location; Mediating; Mental disorders; Molecular; Mus; Mutation; Neuroglia; Neurons; Output; Patients; Play; Process; Property; Protein Isoforms; Proteins; Proteomics; Research; Risk Factors; Role; Series; Signal Transduction; Specificity; Structure; Surface; Synapses; Tertiary Protein Structure; Testing; Variant; Vertebral column; autism spectrum disorder; cell type; conditional knockout; density; dentate gyrus; dosage; experimental study; gamma-Aminobutyric Acid; in vitro Assay; in vivo; insight; light microscopy; memory process; mossy fiber; novel strategies; preservation; protein complex; public health relevance; recruit; relating to nervous system; risk variant; synaptic function; synaptogenesis; trafficking

PROJECT SUMMARY/ABSTRACT Proper brain function requires that neurons make specific types of synapses with specific types of target neurons. Defects in this process of synapse specficity can alter brain activity and may underlie many types of mental illnesses but we know little about the mechanisms by which synapse specificity develops. We recently discovered that the cell adhesion molecule Kirrel3 is selectively required to form a specific type of synapse that connects DG neurons to GABA neurons in the hippocampus. This synapse provides feed-forward inhibition to CA3 and Kirrel3 null mice have significantly elevated CA3 neuron activity. This established Kirrel3 as a functionally relevant target-specific synaptogenic molecule but we still do not know the mechanism of Kirrel3 function. Through a series of in vitro assays, our new preliminary data suggests that Kirrel3 binds other Kirrel3 molecules in cis and trans, directs the assembly of pre- and post-synapses, and its function requires yet to be identified neuronal molecules. Here, we will test the central hypothesis that homophilic, trans-cellular Kirrel3 interactions nucleate DG-to-GABA synapses in vivo by recruiting synaptic proteins to axon-dendrite contact points. In Aim 1, we will determine precisely where, when, and how much Kirrel3 is required to build hippocampal DG-to-GABA synapses in vivo. In Aim 2, we will identify Kirrel3 signaling mechanisms by defining properties controlling the differential subcellular localization of Kirrel3 isoforms and identifing Kirrel3 interacting proteins. Together, the study of Kirrel3 provides a new approach to identify the still elusive mechanisms of target-specific synapse formation and a framework for understanding how changes in synapse specificity impact hippocampal circuit function, which plays a central role in learning and memory processes.

项目总结/摘要 正常的大脑功能需要神经元与特定类型的目标神经元形成特定类型的突触。 这种突触特异性过程的缺陷可以改变大脑活动，并可能成为许多类型的精神障碍的基础。 疾病，但我们对突触特异性发展的机制知之甚少。我们最近发现 细胞粘附分子Kirrel 3被选择性地要求形成一种特定类型的突触， 海马DG神经元对GABA神经元的反应。这种突触提供对CA 3的前馈抑制， Kirrel 3缺失小鼠具有显著升高的CA 3神经元活性。这使得Kirrel 3在功能上成为 相关的靶点特异性突触发生分子，但我们仍然不知道Kirrel 3的功能机制。 通过一系列体外试验，我们的新的初步数据表明，Kirrel 3结合其他Kirrel 3分子 在顺式和反式中，指导突触前和突触后的组装，其功能尚待确定 神经分子在这里，我们将测试中心假设，即嗜同性，跨细胞Kirrel 3相互作用 通过将突触蛋白募集到轴突-树突接触点，使DG-到-GABA突触在体内成核。在目标1中， 我们将精确地确定在何处、何时以及需要多少Kirrel 3来构建海马DG到GABA 体内突触。在目标2中，我们将通过定义控制Kirrel 3信号传导的性质来确定Kirrel 3信号传导机制。 Kirrel 3亚型的差异亚细胞定位和Kirrel 3相互作用蛋白的鉴定。统称 Kirrel 3的研究为识别靶特异性突触的机制提供了一种新的方法 形成和理解突触特异性变化如何影响海马回路的框架 功能，在学习和记忆过程中起着核心作用。