DEVELOPMENTAL CONTROL OF SYNAPSE STRUCTURE WITH LTP

利用 LTP 控制突触结构的发育

基本信息

批准号：
9085412
负责人：
KRISTEN M HARRIS
金额：
$ 37.59万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-09 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9085412
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

项目摘要

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）：树突棘承载 >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正常发展中的作用。长时程增强 (LTP) 是一种非常适合研究这一过程的学习和记忆突触模型。刺被认为很重要，因为它们隔离了持续 > 3 小时的 LTP (L-LTP) 的蛋白质合成依赖性或“晚期”阶段所需的核心结构和分子。清晰的理解需要通过连续切片电子显微镜进行纳米分辨率的 3D 重建，这是本实验室首创的方法。提出了严格的实验来测试树突棘的形成和结构突触可塑性是否为海马体中 L-LTP 的发育调节提供一般机制，海马体是对学习和记忆至关重要的大脑区域。目标 1 是检验以下假设：出生后 (P)12 天 L-LTP 的突然发作与树突棘的首次出现和结构突触可塑性能力相关。实验将确定当一轮 TBS 不产生 L-LTP 时，P12 时的树突、轴突、脊柱和突触结构和组成与 P8 和 P10 有何不同。他们将测试 P12 时 L-LTP 的产生是否会导致小棘的平衡消除和剩余突触的增大（如成熟海马中发生的情况），以及突触前和突触后结构重塑在发育过程中是否与表达 L-LTP 的能力同步。目标 2 是检验以下假设：树突棘由 TBS 诱导，然后在 P10 进行第二次 TBS 后用于维持 L-LTP，但在 P8 时则不然，此时多次 TBS 不会产生 L-LTP。目标 3 是确定小鼠海马中 L-LTP 的发育起始及其超微结构相关性，为未来使用基因操作的工作奠定基础。这些结果有望为学习和记忆的突触基础提供新的见解，这是设计针对发育性脑疾病的有效治疗方法的基本知识。