HOMOSYNAPTIC LTD IN THE HIPPOCAMPUS IN VIVO AND IN VITRO

了解支配活动依赖神经的原理 可塑性对于理解正常和受损的记忆都是不可或缺的 功能。这里提出的研究的总体目标是研究 同形突触长时效应的前提条件和潜在机制 体内海马区连合-CA1突触的抑制(LTD)。 同源突触有限公司是突触传递的持久减少， 由传入通路中的活动引起。用形式模型进行研究 学习和记忆的研究表明，突触的力量必须 容量以依赖于使用的方式同时减少和增加 成功地模拟了这些认知过程。通过以下方式研究 在体外维持的前脑突触已经证明同源突触 LTD确实发生了，当兴奋性突触时，它的诱导更受欢迎 在超极化或衰减去极化期间发生激活 突触后细胞，它的诱导需要提升 突触后钙水平。人们对此知之甚少，而且 同源突触LTD在活体前脑中的表达最近的实验 在完整的海马体中的连合-CA1突触表明 强健的LTD是通过刺激连合在该突触上产生的 利用使用刺激间间隔(ISI)的脉冲对进行传入 第二次脉冲对CA1区锥体细胞放电的抑制 一双。当ISI延长和锥体细胞时，NO LTD发展 第二次脉冲诱发的放电不受抑制，或者当钙离子- 通透性N-甲基-D-天冬氨酸(NMDA)受体被阻断。为了获得 对成对脉冲刺激机制的进一步洞察 Induces Ltd，这里提出的第一项研究将评估 双脉冲抑制与LTD诱导的相关性。这个 第二项研究将探索成对脉冲背后的机制 抑制；一个可能的候选是前馈和重复的抑制 局部神经元间，因为神经元之间的相互连接的性质 中间神经元和锥体细胞。第三项研究将确定 或者不需要这一机制的贡献来诱导 LTD为双脉冲刺激。以启用对贡献的分析 在单细胞水平上的机制，第四项研究将有助于 一种研究双脉冲刺激诱发大鼠LTD的方法 海马区脑片制备。使用这一方案，最终研究将 检测成对脉冲刺激是否诱导LTD 需要突触后钙，这一现象表明 依赖于NMDA受体的激活。总而言之，这些发现 从这些研究中获得的信息将增强我们对神经的理解 学习和记忆的基础过程。

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.