DEVELOPMENTAL CONTROL OF SYNAPSE STRUCTURE WITH LTP

描述（由申请人提供）：树突棘宿主> 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正常发展中的作用。长时程增强（LTP）是一种非常适合研究学习记忆过程的突触模型。棘被认为是重要的，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。一个清晰的理解需要从连续切片电子显微镜，在这个实验室开创的方法的三维重建的纳米分辨率。提出了严格的实验，以测试是否形成树突棘和结构突触可塑性提供一般机制的L-LTP在海马，一个大脑区域的学习和记忆的关键发育调控。目的1是验证L-LTP在出生后12天突然发作与树突棘的首次出现和结构突触可塑性能力有关的假设。该实验将确定当一次TBS不产生L-LTP时，P12与P8和P10的树突、轴突、棘和突触结构和组成的区别。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扩大，就像在成熟海马中发生的那样，以及突触前和突触后结构重塑是否在发育过程中与表达L-LTP的能力同步。目的2是测试树突棘由TBS诱导，然后在P10第二轮TBS后用于维持L-LTP，但在P8时不起作用的假设，此时多次TBS不产生L-LTP。目的3是确定L-LTP在小鼠海马中的发育起始及其超微结构相关性，为将来使用遗传操作的工作奠定基础。这些结果有望对学习和记忆的突触基础产生新的见解，这是设计有效治疗发育性大脑疾病的基本知识。

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.