Spine and Synaptic Plasticity in Mature Hippocampus

成熟海马的脊柱和突触可塑性

• 批准号: 7463834
• 负责人: KRISTEN M HARRIS
• 金额: $ 25.84万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463834
• 关键词: Address; Adult; Animals; Back; Biological Models; Brain; Brain Pathology; Cadherins; Cell Adhesion; Cell Adhesion Molecules; Chemosensitization; Chromosome Pairing; Contralateral; DLG4 gene; Dendrites; Dendritic Spines; Dependence; Depressed mood; Development; Docking; Electron Microscopy; Endocytosis; Endosomes; Ensure; Filopodia; Frequencies; 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; Numbers; Pathway interactions; Perforant Pathway; Perforation; Phase; Play; Polyribosomes; Population; Process; Protein Biosynthesis; Proteins; Rattus; Research; Research Personnel; Role; Signal Transduction; Slice; Specific qualifier value; Structure; Synapses; Synaptic plasticity; Testing; Thinking; Time; To specify; Translating; Vertebral column; Vesicle; awake; base; calmodulin-dependent protein kinase II; density; dentate gyrus; design; postsynaptic; presynaptic; programs; receptor; relating to nervous system; research study; response; scaffold; size

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）：这项研究的长期目标是明确大脑中突触结构的变化，这些变化支持学习和记忆。长期以来，人们一直认为突触数量或大小的变化是记忆的基础，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，而且在哺乳动物中，相关回路不容易指定。为了简化这一任务，模型系统海马长期增强（LTP）被用来研究这些突触机制。LTP是一种蛋白质合成依赖性突触效能增强，可以持续数月，有大量证据表明它在学习和记忆中起着重要作用。多核糖体（PR）是合成新蛋白质的结构。在未成熟大鼠海马LTP切片中，树突棘获得PR，其突触扩大。切片实验缺少关于突触变化是否持续超过几个小时的信息，这些变化是否完全是发育性的，以及类似的变化是否发生在整个动物身上。本实验旨在研究成熟大鼠内侧穿通通路高频刺激后LTP后海马齿状回的突触。在LTP诱导后30分钟至3个月，采用定量序列电镜和免疫金标技术区分LTP不同阶段突触结构和组成的变化。将比较增强的内侧穿孔通路突触、对侧控制内侧穿孔通路突触和相邻的外侧穿孔通路和近端异突触抑制的关联突触。具体目的包括：1)检测LTP过程中发生蛋白质合成的脊髓突触扩大。2)研究突触穿孔、小刺形成和细胞粘附在LTP过程中突触扩大和突触重塑的分子成分中的作用。3)确定LTP期间新的树突是否会增强连接。4)测试NMDA受体对结构和分子变化的依赖性，以确保它们与突触可塑性有关，而不是简单地由神经活动驱动。了解LTP期间的结构可塑性将阐明正常变化的机制，作为理解脑病理学的基础。