DEVELOPMENTAL CONTROL OF SYNAPSE STRUCTURE WITH LTP

利用 LTP 控制突触结构的发育

• 批准号: 8508316
• 负责人: KRISTEN M HARRIS
• 金额: $ 36.07万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508316
• 关键词: Address; Age; Area; Axon; Biological Models; Brain; Brain Diseases; Brain region; Dendrites; Dendritic Spines; Development; Developmental Process; Electron Microscopy; Equilibrium; Excitatory Amino Acid Antagonists; Excitatory Synapse; Filopodia; Foundations; Future; Goals; Hippocampus (Brain); Hour; In Vitro; Individual; Knowledge; Laboratories; Lead; Learning; Length; Long-Term Potentiation; Memory; Modeling; Mus; N-Methylaspartate; Nervous System Physiology; Neuraxis; Neurons; Outcome; Pattern; Perfusion; Phase; Process; Production; Property; Protein Biosynthesis; Protocols documentation; Rattus; Regulation; Resolution; Role; Shapes; Site; Slice; Structure; Sum; Synapses; Synaptic Vesicles; Synaptic plasticity; Testing; Vertebral column; Work; base; design; developmental disease; effective therapy; genetic manipulation; in vivo; insight; nanometer; postnatal; postsynaptic; presynaptic; reconstruction; research study; synaptogenesis

DESCRIPTION (provided by applicant): Dendritic spines host >90 percent of excitatory synapses; they are lost or have abnormal structure in many developmental disorders that disrupt central nervous system function. The overall goal is to understand the role of spine and synapse structure in the normal development of learning and memory. Long-term potentiation (LTP) is a synaptic model of learning and memory well-suited to investigate this process. Spines are thought to be important because they sequester core structures and molecules needed for the protein synthesis-dependent or "late" phase of LTP (L-LTP) lasting >3hr. A clear understanding requires the nanometer resolution of 3D reconstruction from serial section electron microscopy, an approach pioneered in this laboratory. Rigorous experiments are proposed to test whether formation of dendritic spines and structural synaptic plasticity provide general mechanisms for the developmental regulation of L-LTP in hippocampus, a brain region crucial for learning and memory. Aim 1 is to test the hypothesis that the abrupt onset of L-LTP at postnatal day (P)12 is associated with first occurrence of dendritic spines and capacity for structural synaptic plasticity. The experiments will determine what differentiates dendritic, axonal, spine, and synaptic structure and composition at P12, from P8 and P10 when L-LTP is not produced by one bout of TBS. They will test whether production of L-LTP at P12 results in a balanced elimination of small spines and enlargement of remaining synapses as occurs in mature hippocampus and whether pre- and postsynaptic structural remodeling are synchronized during development with the ability to express L-LTP. Aim 2 is to test the hypothesis that dendritic spines are induced by TBS and then serve to sustain L-LTP after a second bout of TBS at P10, but not at P8, when multiple TBS do not produce L-LTP. Aim 3 is to ascertain the developmental onset of L-LTP and its ultrastructural correlates in mouse hippocampus as a foundation for future work using genetic manipulations. The outcomes promise new insight into the synaptic basis of learning and memory, essential knowledge to design effective treatments for developmental brain disorders.

描述（由申请人提供）：树突状刺宿主> 90％的兴奋性突触；它们在许多破坏中枢神经系统功能的发育障碍中丢失或具有异常结构。总体目标是了解脊柱和突触结构在学习和记忆的正常发展中的作用。长期增强（LTP）是一种学习和记忆非常适合研究此过程的突触模型。人们认为棘是很重要的，因为它们隔离了持续> 3hr的LTP（L-LTP）的蛋白质合成依赖性或“晚期”期所需的核心结构和分子。清楚的理解需要从串行部分电子显微镜中对3D重建的纳米分辨率，这是该实验室中率先使用的方法。提出了严格的实验来测试树突状刺和结构突触可塑性的形成是否为L-LTP发育调控的一般机制是海马的，这是对学习和记忆至关重要的大脑区域。目的1是测试以下假设：产后（p）12在产后（p）12的突然发作与树突棘的首次出现和结构突触可塑性的能力有关。这些实验将确定当p12和p10与p8和p10的树突状，轴突，脊柱和突触结构和组成区别时，当L-LTP不是由TBS的一回合产生时。他们将测试在p12处的L-LTP的产生是否会导致消除小刺，并像成熟海马中发生的剩余突触增大，以及在发育过程中与表达L-LTP的能力同步的突触前和突触后结构重塑。 AIM 2是测试以下假设：树突状棘是由TBS诱导的，然后在P10处第二次回合TBS后维持L-LTP，而在P8处则不在P8，当多个TBS不产生L-LTP时。 AIM 3是确定L-LTP的发育开始及其在小鼠海马中的超微结构相关性，作为使用遗传操作的未来工作的基础。结果有望对学习和记忆的突触基础的新见解，为发育性脑部疾病设计有效治疗的基本知识。