COMPONENTS OF HIPPOCAMPAL SYNAPTIC PLASTICITY

记忆障碍是最早也是最令人衰弱的特征之一 阿尔茨海默病(AD)。最终改善或逆转记忆 功能障碍，并理解为什么它如此显著地参与AD，它 将是更好地理解记忆的潜在机制所必需的。长- 术语增强(LTP)是突触可塑性的一种依赖于使用的形式 这是记忆存储的细胞基础的一部分，人们对此非常感兴趣。 这是突触效能的持续增加。作为确定 它的基本机制，这个项目的目标是测试 假设LTP不是一个单一的过程，而是由4个不同的过程组成 组件。其组件的标识将在 未来通过进一步研究每个组件的基础机制，如 以及它们如何随着年龄的增长和AD的变化而改变。细胞外和 大鼠CA1区全细胞膜片钳记录 海马区脑片制备。 短时程增强(STP)是突触效能的增加， 在大约15分钟内返回到基线。它一直被认为是 阈值以下刺激引起的LTP的一种递减形式。初步 然而，数据表明，STP可能是单独表达的成分 可塑性。具体目标1是检验STP是一种 通过比较将增强成分从LTP中分离出来，但相关的成分 STP和LTP重叠区诱导和表达的五个步骤 和不同。 几种类型的实验表明，LTP可能由早期 (&lt；1/2-2小时)和后期。初步数据显示，早期的LTP 表达改变成对脉冲促进(PPF)，一种突触前形式 增强，这表明早期LTP表达包括 突触前轨迹。具体目标2是使用PPF来检验假设 持续的LTP由两个组成部分组成：早期的、第二个信使 中介性突触前成分和晚期突触后成分。 长期抑郁(LTD)是突触效能的持续下降 这可能会延长学习的能力，也可能会导致遗忘。它的 潜在的机制可能仅仅是LTP的逆转，或者它可能是 突触可塑性的单独成分。初步数据显示， LTD增加了PPF，这表明它的表达位点，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成分 考察它们之间的两个相互作用，以及它们对PPF的影响。 如果LTP由多个组件组成，则必须确定 并描述它们的特征，因为每一个都可能为 突触可塑性和记忆的治疗干预。

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.