COMPONENTS OF HIPPOCAMPAL SYNAPTIC PLASTICITY

海马突触可塑性的组成部分

• 批准号: 2431216
• 负责人: PAUL E SCHULZ
• 金额: $ 10.26万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2431216
• 关键词: NMDA receptors; bicuculline; calcium flux; electrostimulus; enzyme activity; excitatory aminoacid; extracellular; hippocampus; laboratory rat; long term potentiation; microelectrodes; nerve threshold; neural facilitation; neural plasticity; neuropharmacology; nifedipine; picrotoxin; protein kinase A; synapses; voltage /patch clamp; voltage gated channel

Memory dysfunction is one of the earliest and most debilitating features of Alzheimer's disease (AD). To eventually improve or reverse memory dysfunction, and to understand why it is so prominently involved in AD, it will be necessary to better understand mechanisms underlying memory. Long- term potentiation (LTP) is a use-dependent form of synaptic plasticity that is of great interest as part of the cellular basis of memory storage. It is a sustained increase in synaptic efficacy. As a step in identifying its underlying mechanisms, the goal of this project is to test the hypothesis that LTP is not a unitary process, but consists of 4 distinct components. Identification of its components will be followed in the future by further study of the mechanisms underlying each component, as well as how they may be altered by aging and in AD. Extracellular and whole-cell patch clamp recordings will be made from area CA1 in the rat hippocampal slice preparation. Short-term potentiation (STP) is an increase in synaptic efficacy that returns to baseline in approximately 15 minutes. It has been assumed to be a decremental form of LTP induced by subthreshold stimulation. Preliminary data, however, suggest that STP may be a separately expressed component of plasticity. Specific Aim 1 is to test the hypothesis that STP is a separate, but related, component of potentiation from LTP by comparing five steps in STP and LTP induction and expression for areas of overlap and difference. Several types of experiments have suggested that LTP may consist of early (< 1/2-2hrs) and late phases. Preliminary data suggests that early LTP expression alters paired-pulse facilitation (PPF), a presynaptic form of potentiation, suggesting that early LTP expression includes the presynaptic locus. Specific Aim 2 is to use PPF to test the hypothesis that sustained LTP consists of two components: an early, second messenger mediated, presynaptic component, and a late postsynaptic component. Long-term depression (LTD) is a sustained decrease in synaptic efficacy that may extend the capacity for learning or underlie forgetting. Its underlying mechanism may simply be a reversal of LTP, or it may be a separate component of synaptic plasticity. Preliminary data suggest that LTD increases PPF suggesting that its loci of expression, like LTP, includes the presynaptic site. Specific Aim 3 is to test the hypothesis that LTP and LTD are two independent components of synaptic plasticity by examining two interactions between them, and their effects on PPF. If LTP consists of several components, it would be important to identify and characterize them because each might provide unique sites for therapeutic intervention in synaptic plasticity and memory.

记忆功能障碍是最早也是最使人衰弱的特征之一 阿尔茨海默病（AD）。最终改善或逆转记忆 功能障碍，并了解为什么它在 AD 中如此显着地参与， 对于更好地理解记忆背后的机制是必要的。长的- 术语增强（LTP）是突触可塑性的一种依赖于使用的形式 作为记忆存储的细胞基础的一部分，这是非常有趣的。 这是突触功效的持续增加。作为识别的一个步骤 其基本机制，该项目的目标是测试 假设 LTP 不是一个单一的过程，而是由 4 个不同的过程组成 成分。其成分的识别将在 未来通过进一步研究每个组成部分的机制， 以及它们如何因衰老和AD而改变。细胞外和 全细胞膜片钳记录将从大鼠的 CA1 区进行 海马切片准备。 短期增强（STP）是突触功效的增加， 大约 15 分钟后恢复到基线。它被假设为 由阈下刺激引起的 LTP 递减形式。初步的 然而，数据表明 STP 可能是单独表达的组成部分 可塑性。具体目标 1 是检验 STP 是一个假设 通过比较，从 LTP 中分离出但相关的增强成分 STP 和 LTP 重叠区域诱导和表达的五个步骤 和差异。 几种类型的实验表明，LTP 可能包括早期 （< 1/2-2 小时）和后期。初步数据表明早期 LTP 表达改变配对脉冲促进（PPF），一种突触前形式 增强作用，表明早期 LTP 表达包括 突触前位点。具体目标2是使用PPF来检验假设 持续的 LTP 由两个部分组成：早期第二信使 介导的突触前成分和晚期突触后成分。 长期抑郁（LTD）是突触功效持续下降 这可能会扩展学习能力或成为遗忘的基础。它是 潜在机制可能只是 LTP 的逆转，也可能是 突触可塑性的独立组成部分。初步数据表明 LTD 增加 PPF，表明其表达位点（如 LTP） 包括突触前部位。具体目标 3 是检验假设 LTP 和 LTD 是突触可塑性的两个独立组成部分 检查它们之间的两种相互作用以及它们对 PPF 的影响。 如果 LTP 由多个组件组成，那么确定 并描述它们的特征，因为每个都可能提供独特的站点 突触可塑性和记忆的治疗干预。