HOMOSYNAPTIC LTD IN THE HIPPOCAMPUS IN VIVO AND IN VITRO

了解支配活动依赖性神经系统的原理 可塑性对于理解正常和受损的记忆是不可或缺的 功能 这里提出的研究的总体目标是检查 同源突触长时程的先决条件和潜在机制 抑郁症（LTD）在连合CA 1突触在体内海马。 同突触LTD是突触传递的持续减少， 是由传入通路的活动引起的。 使用正式模型进行研究 学习和记忆的研究表明， 以使用依赖的方式减少和增加的能力， 这些认知过程的成功模拟。 研究与 在体外维持的前脑突触已经证明， LTD确实发生，当兴奋性突触 激活发生在超极化或衰减去极化期间， 突触后细胞，其诱导需要升高 突触后钙水平。 关于归纳和 在体前脑中同源突触LTD的表达。 最近的实验 与完整海马体中的连合-CA 1突触的关系表明， 通过刺激连合，在突触处诱导了鲁棒LTD 使用刺激间隔（ISI）的脉冲对传入， 导致抑制由第二脉冲诱发的CA 1锥体细胞放电 一对。 当ISI延长且锥体细胞 由第二脉冲诱发的放电不被抑制，或者当钙- 可渗透的N-甲基-D-天冬氨酸（NMDA）受体被阻断。 获得 进一步深入了解双脉冲刺激的机制 诱导LTD，这里提出的第一项研究将评估 配对脉冲抑制与LTD诱导之间的相关性。 第二项研究将探讨双脉冲的机制 抑制;一个可能的候选者是前馈和复发性抑制， 局部中间神经元，因为它们之间的相互连接性， 中间神经元和锥体细胞。 第三项研究将确定是否 是否需要该机制的贡献来诱导 LTD的双脉冲刺激。 为了能够分析贡献 在单细胞水平上的机制，第四项研究将有助于开发 一个研究方案，用于研究LTD诱导的成对脉冲刺激，在 海马切片制备。 使用该方案，最终研究将 检查是否通过双脉冲刺激诱导LTD 需要突触后的钙，这一现象表明， 依赖于NMDA受体激活。 总的来说， 从这些研究中获得的信息将增强我们对神经系统的理解。 是学习和记忆的基础

Knowledge of the principles that govern activity-dependent neural plasticity is integral to understanding both normal and impaired memory function. The overall goal of the studies proposed here is to examine the prerequisite conditions and underlying mechanisms of homosynaptic long-term depression (LTD) at the commissural-CA1 synapse in the hippocampus in vivo. Homosynaptic LTD is a lasting decrease in synaptic transmission that results from activity in the afferent pathway. Research with formal models of learning and memory has shown that synaptic strength must have the capacity to both decrease and increase in a use-dependent manner for successful simulation of these cognitive processes. Research with forebrain synapses maintained in vitro has demonstrated that homosynaptic LTD does occur, that its induction is favored when excitatory synaptic activation occurs during hyperpolarization or attenuated depolarization of the postsynaptic cell, and that its induction requires elevation of postsynaptic calcium levels. Little is known about the induction and expression of homosynaptic LTD in forebrain in vivo. Recent experiments with the commissural-CA1 synapse in the intact hippocampus have shown that robust LTD is induced at that synapse by stimulation of the commissural afferents with pairs of pulses using an interstimulus interval (ISI) that causes inhibition of CA1 pyramidal cell firing evoked by the second pulse of a pair. No LTD develops when the ISI is lengthened and pyramidal cell firing evoked by the second pulse is not inhibited, or when the calcium- permeable N-methyl-D-aspartate (NMDA) receptors is blocked. To gain further insights into the mechanisms by which paired-pulse stimulation induces LTD, the first study proposed here will assess the degree of correlation between paired-pulse inhibition and the induction of LTD. The second study will explore the mechanism that underlies paired-pulse inhibition; a likely candidate is feedforward and recurrent inhibition from local interneurons, because of the nature of the interconnectivity between interneurons and pyramidal cells. The third study will determine whether or not the contribution of this mechanism is required for the induction of LTD by paired-pulse stimulation. To enable analysis of contributing mechanisms at he single-cell level, the fourth study will serve to develop a protocol for studying LTD induced by paired-pulse stimulation in the hippocampal slice preparation. Using this protocol, the final study will examine whether or not the induction of LTD by paired-pulse stimulation requires postsynaptic calcium, as is suggested by the phenomenon's dependence on NMDA receptor activation. Collectively, the findings obtained from these studies will enhance our understanding of the neural processes that underlie learning and memory.