Mechanisms of SynCAM-Induced Synapse Formation

SynCAM 诱导突触形成的机制

• 批准号: 7017043
• 负责人: Thomas Biederer
• 金额: $ 27.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017043
• 关键词: affinity chromatography; biological signal transduction; cell adhesion molecules; central nervous system; confocal scanning microscopy; developmental neurobiology; drug addiction; fluorescence microscopy; genetically modified animals; glycosylation; hippocampus; intermolecular interaction; laboratory mouse; laboratory rat; learning; memory; neural plasticity; neurogenesis; synaptogenesis; western blottings

DESCRIPTION (provided by applicant): Neurons communicate with each other through synapses. Synapses are formed by both a presynaptic neuron and a postsynaptic neuron. During development of the central nervous system (CNS), countless new synapses are established, and new synapses continue to form throughout life. The long-term goal of this application is to determine the molecular basis of synapse formation in the vertebrate CNS. Recently, the first proteins have been identified that initiate the formation of synapses. One is SynCAM, a synaptic cell adhesion molecule that connects pre- and postsynaptic sides. Importantly, SynCAM induces the formation of new, fully functional synapses. It is highly expressed in the developing CNS during intense synaptogenesis, indicating a function for this molecule in synapse formation throughout the brain. The objective of this application is to determine the extra- and intracellular interactions of SynCAM that initiate synapses, and to characterize them further. Achieving these goals is important for human health. Alterations in synapse formation affect synaptic plasticity, which is associated with changes in human behavior, learning and memory, and addiction. Furthermore, deficits of synapse formation and synaptic loss have been suggested for neurodevelopmental and neurodegenerative diseases. To attain the objective of this application, three aims are pursued. First, the role of adhesion and signaling molecules in CNS synapse formation is examined. The experiments involve biochemical characterization of SynCAM and the functional analysis of its extracellular interactions in cultured hippocampal neurons. Second, the intracellular SynCAM interactions driving synaptic membrane specializations are determined. These experiments involve the purification and characterization of intracellular binding partners of SynCAM from brain. Third, the site of SynCAM action in pre- and postsynaptic membrane specialization is analyzed. These studies are not only conducted in cultured neurons, but also in genetically altered mice to manipulate synapse formation in vivo and to test effects on synaptic plasticity and brain development. In summary, this application aims to identify the molecular interactions involved in CNS synapse formation, which will allow testing whether these processes are affected in disorders of the human brain.

描述（由申请人提供）： 神经元通过突触相互通信。突触前神经元和突触后神经元形成突触。在中枢神经系统（CNS）的开发过程中，建立了无数的新突触，并在整个生命中继续形成新的突触。该应用的长期目标是确定脊椎动物中枢神经系统中突触形成的分子基础。最近，已经确定了启动突触形成的第一个蛋白质。一个是连接突触前和突触后侧的突触细胞粘附分子的Syncam。重要的是，Syncam诱导了新的功能性突触的形成。它在强烈的突触发生过程中在发育中的CNS中高度表达，表明该分子在整个大脑中的突触形成中的功能。该应用的目的是确定启动突触的Syncam的细胞外和细胞内相互作用，并进一步表征它们。实现这些目标对于人类健康很重要。突触形成的改变会影响突触可塑性，这与人类行为，学习和记忆以及成瘾的变化有关。此外，已经建议神经发育和神经退行性疾病的突触形成和突触丧失的缺陷。为了实现本申请的目标，实现了三个目标。首先，检查了粘附和信号分子在中枢神经系统突触形成中的作用。该实验涉及Syncam的生化表征以及其在培养的海马神经元中其细胞外相互作用的功能分析。其次，确定了驱动突触膜专业的细胞内联合相互作用。这些实验涉及从大脑的syncam的细胞内结合伴侣的纯化和表征。第三，分析了突触前膜专业和后膜专业方面的同步作用部位。这些研究不仅在培养的神经元中进行，而且在遗传上改变的小鼠中以操纵体内突触形成并测试对突触可塑性和脑发育的影响。总而言之，该应用旨在确定中枢神经系统突触形成所涉及的分子相互作用，这将允许测试这些过程是否受到人脑疾病的影响。