Spine and Synaptic Plasticity in Mature Hippocampus

成熟海马的脊柱和突触可塑性

• 批准号: 7820172
• 负责人: KRISTEN M HARRIS
• 金额: $ 36.79万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820172
• 关键词: Address; Adult; Animals; Back; Biological Models; Brain; Cadherins; Cell Adhesion; Cell Adhesion Molecules; Chemosensitization; DLG4 gene; Dendrites; Dendritic Spines; Dependence; Development; Docking; Electron Microscopy; Endocytosis; Endosomes; Ensure; Filopodia; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Hour; In Vitro; Label; Lateral; Learning; Long-Term Depression; Long-Term Potentiation; Maintenance; Mammals; Measures; Medial; Memory; Mitochondria; Molecular; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neurons; Pathway interactions; Perforant Pathway; Perforation; Phase; Play; Polyribosomes; Population; Process; Proteins; Rattus; Research; Role; Signal Transduction; Slice; Structure; Synapses; Synaptic plasticity; Testing; Time; To specify; Translating; Vertebral column; Vesicle; awake; calmodulin-dependent protein kinase II; density; dentate gyrus; design; postsynaptic; presynaptic; receptor; relating to nervous system; research study; response; scaffold

DESCRIPTION (provided by applicant): The long-term goal of this research is to specify changes in synapse structure in the brain that subserve learning and memory. Changes in synapse number or size have long been thought to underpin memory, but this hypothesis has not been proven because structural changes are difficult to measure, the altered synapses are difficult to identify, and the relevant circuits are not easily specified in mammals. To simplify this task the model system hippocampal long-term potentiation (LTP) is used to investigate these synaptic mechanisms. LTP is a protein synthesis-dependent enhancement in synaptic efficacy that can persist for months and there is abundant evidence that it plays an important role in learning and memory. Polyribosomes (PR) are structures where new proteins are synthesized. A discrete population of dendritic spines acquires PR and their synapses enlarge during LTP in hippocampal slices from immature rats. Missing from the slice experiments is information about whether the synaptic changes are sustained beyond several hours, whether the changes are strictly developmental, and whether similar changes occur in whole animals. The present experiments are designed to investigate synapses in the hippocampal dentate gyrus from mature rats that have undergone LTP after high-frequency stimulation in the medial perforant path. Quantitative serial electron microscopy and immunogold labeling will be used to distinguish changes in synapse structure and composition during different phases of LTP from 30 minutes to 3 months after its induction. Comparisons will be made between the potentiated medial perforant path synapses, the contralateral control medial perforant path synapses and the neighboring lateral perforant path and proximal associational synapses that become heterosynaptically depressed. Specific aims include: 1) Test for synapse enlargement at spines undergoing protein synthesis during LTP. 2) Investigate roles for synapse perforation, spinule formation, and cell adhesions in synapse enlargement and molecular components of synaptic remodeling during LTP. 3) Determine whether new dendritic protrusions give rise to enhanced connectivity during LTP. 4) Test NMDA receptor-dependence of structural and molecular changes to ensure they are related to synaptic plasticity, and not simply driven by neural activity. Understanding structural plasticity during LTP will elucidate mechanisms underlying normal changes as a basis for understanding brain pathology.

描述（由申请人提供）：本研究的长期目标是明确有助于学习和记忆的大脑突触结构的变化。长期以来，突触数量或大小的变化一直被认为是记忆的基础，但这一假设尚未得到证实，因为结构变化难以测量，改变的突触难以识别，并且相关的回路在哺乳动物中不容易指定。为了简化这一任务的模型系统海马长时程增强（LTP）被用来研究这些突触机制。LTP是一种蛋白质合成依赖性的突触效能增强，可以持续数月，并且有大量证据表明它在学习和记忆中起重要作用。多核糖体（PR）是合成新蛋白质的结构。在未成熟大鼠海马脑片LTP过程中，树突棘的离散群体获得PR，并且它们的突触扩大。切片实验中缺少的是关于突触变化是否持续超过几个小时的信息，这些变化是否是严格的发育变化，以及类似的变化是否发生在整个动物身上。本实验旨在研究高频刺激大鼠内侧穿通径后LTP过程中海马齿状回突触的变化，采用定量连续电镜和免疫金标记技术观察LTP过程中突触结构和成分的变化。将进行比较之间的增强内侧穿通路径突触，对侧控制内侧穿通路径突触和相邻的外侧穿通路径和近端关联突触，成为异突触抑制。具体目标包括：1）测试LTP期间经历蛋白质合成的棘处的突触扩大。2)研究突触穿孔、小刺形成和细胞粘附在LTP期间突触扩大和突触重塑的分子成分中的作用。3)确定新的树突状突起是否在LTP期间引起增强的连接。4)测试结构和分子变化的NMDA受体依赖性，以确保它们与突触可塑性有关，而不仅仅是由神经活动驱动。了解LTP过程中的结构可塑性将阐明正常变化的机制，作为了解大脑病理学的基础。