DYNAMICS OF CNS SYNAPSE DEVELOPMENT

描述：这项研究计划的长期目标是确定 调节细胞和分子机制的形成和 中枢神经系统组织中突触连接的可塑性。目前的建议 将专注于主要突触后特化的发展 中枢神经系统，树突的脊椎。首席调查员的前科 观察发现了三种不同类型的带刺突起 (丝足、原棘和棘突)发育中的海马树突上； 这些突出物具有不同的动态属性(每个类 逐渐变得更稳定)，并在 发展。这一发展进程在时间上与 树突上突触的形成，但功能关系 在树突结构变化、突触接触形成和 人们对突触活动知之甚少。首席调查员将 使用时间推移共聚焦显微镜，电子显微镜， 免疫细胞化学，以及生理和分子方面的扰动 体外大鼠海马片和细胞培养：(1)更好地确定 突触形成与树突棘的时空关系 发育，以及(2)确定细胞-细胞接触和突触 活性可能调节细胞的形态和分子发育。 脊椎。首席调查员的主要假设是新生的 突触接触是在结构动态的脊柱前体上形成的， 这些新生触点上的突触活动可以调节 脊柱结构的发育可塑性，这种调节是 部分是通过控制神经细胞黏附的表达来介导的 树枝状表面的分子。从这些信息中获得的新信息 研究应该使人们更全面地理解对 突触发育，以及突触变化之间的关系 结构和功能。突触后脊椎形态异常和 密度在各种发育障碍中都有记录， 神经病理情况，如智力低下、阿尔茨海默氏症 疾病和颞叶癫痫。此外，突触的变化 结构和数字被认为是正常心理过程的基础，例如 作为学习和记忆。因此，这些研究可以提供重要的 突触发育和可塑性的基本机制 在人类的各种正常和非正常情况下工作。

DESCRIPTION: The long term goal of this research program is to identify cellular and molecular mechanisms that regulate the formation and plasticity of synaptic connections in CNS tissue. The present proposal will focus on the development of the major postsynaptic specialization in the CNS, the dendritic spine. The principal investigator's previous observations identified three distinct classes of spiny protrusions (filopodia, protospines, and spines) on developing hippocampal dendrites; these protrusions have different dynamic properties (each class progressively more stable), and they emerge sequentially during development. This developmental progression coincides in time with the formation of synapses on dendrites, but the functional relationships between dendritic structure changes, synaptic contact formation, and synaptic activity are poorly understood. The principal investigator will use time-lapse confocal microscopy, electron microscopy, immunocytochemistry, and physiological and molecular perturbations in in vitro rat hippocampal slice and cell cultures to (1) better define the spatiotemporal relationship between synapse formation and dendritic spine development, and (2) determine how cell-cell contacts and synaptic activity may regulate the morphological and molecular development of spines. The principal investigator's primary hypothesis is that nascent synaptic contacts are formed on structurally-dynamic spine precursors, that synaptic activity at these nascent contacts can regulate the developmental plasticity of spine structure, and that this regulation is mediated, in part, by controlling the expression of neural cell adhesion molecules on dendritic surfaces. New information gained from these studies should lead to a fuller understanding of the regulation of synaptic development, and of the relationships between changes in synaptic structure and function. Abnormalities in postsynaptic spine morphology and density have been documented in a variety of developmental disorders and neuropathological conditions such as mental retardation, Alzheimer's Disease, and temporal lobe epilepsy. Moreover, change in synaptic structure and number are thought to underlie normal mental processes, such as learning and memory. Hence, these studies could provide important insight on fundamental mechanisms of synaptic development and plasticity operating over a wide range of normal and abnormal conditions in man.