Temporal requirements for N-cadherin in maintaining stability of synapses

描述（由申请人提供）：有充分证据表明，细胞粘附分子n -钙粘蛋白是早期大脑发育和突触连接建立所必需的。然而，它在突触初始发育和成熟后维持突触形式和功能的作用仍然是一个悬而未决的问题。这在哺乳动物大脑中尚不清楚，因为先前用于修饰n -钙粘蛋白功能的遗传操作会导致大脑组织的广泛扰动，是胚胎致命的，或者不是n -钙粘蛋白特异性的。本提案的总体目标是了解n -钙粘蛋白对早期发育后大脑突触分子组成和稳定性的贡献，使用在出生后第三周开始的n -钙粘蛋白条件缺失小鼠。分子技术将与免疫细胞化学和显微镜结合使用，以确定n -钙粘蛋白影响突触稳定性和组织的程度。该提案还将研究n -钙粘蛋白的不同功能域如何通过利用具有修改或缺失特定结构域的突变n -钙粘蛋白结构来促进突触维持。利用这一策略，可以绕过N-cadherin在基本脑结构、迁移、轴突生长和突触发生中的复杂作用，从而研究N-cadherin选择性地对维持突触组成和稳定性很重要的假设。相关性：突触连通性的中断可能是精神疾病的核心，这些疾病在早期发育时期之后表现出来，包括精神分裂症、自闭症谱系障碍和Rett综合征等疾病。确定像钙粘蛋白这样的突触蛋白在维持突触结构和连接中所起的基本作用，可以帮助我们更好地理解其功能障碍是如何导致精神疾病的。

DESCRIPTION (provided by applicant): It is well documented that the cell adhesion molecule N-cadherin is required for early brain development and establishment of synaptic connectivity. However, its role in maintaining synaptic form and function beyond initial synapse development and in maturity remains an open question. This is unclear in mammalian brain because genetic manipulations that have been used previously to modify N-cadherin function lead to extensive perturbations of brain organization, are embryonic lethal, or are not specific to N-cadherin. The overall goal of this proposal is to understand the contributions of N-cadherin to synapse molecular composition and stability in the post-early developmental brain using mice harboring a conditional deletion of N-cadherin which commences in the third postnatal week. Molecular techniques will be used in conjunction with immunocytochemistry and microscopy to determine the extent to which N-cadherin affects synapse stability and organization. This proposal will also look at how N-cadherin's different functional domains contribute to synapse maintenance by utilizing mutant N-cadherin constructs that have a modified or are missing a particular domain. Using this strategy, the confounding antecedent roles of N-cadherin in development of basic brain structure, migration, axon growth and synaptogenesis can be bypassed to investigate the hypothesis that N-cadherin, selectively, is important for maintenance of synapse composition and stability. Relevance: Disruptions in synapse connectivity may be central to psychiatric diseases which manifest themselves after the period of early development, and include such disorders as schizophrenia, autism spectrum disorders, and Rett syndrome. Determining the fundamental role that synaptic proteins such as cadherins play in maintaining synapse architecture and connections can help us better understand how its dysfunction leads to psychiatric disorders.