LONGTERM DEPRESSION IN THE ADULT HIPPOCAMPUS IN VIVO

描述（研究者摘要）：了解 活动依赖性神经可塑性是理解 正常和受损的记忆功能。 的总体目标 在这项拨款申请中提出的实验是研究参数 关键的诱导和生化过程的基础 突触长时程抑制（LTD）的维持和表达 成年人海马体中的突触强度。 学习和记忆的正式模型的研究表明， 强度必须有能力既减少和增加， 使用依赖的方式来成功模拟这些认知过程。 诱导LTD的常见范例是递送延长的 低频刺激传入通路。 然而，LTD在 已经发现这种方式仅发生在体外制剂中， 年轻动物的组织。 我们最近已经证明， 连合通路的成对脉冲刺激可靠地诱导鲁棒的 成人海马CA 1锥体细胞连合输入的LTD in vivo. 随后的实验表明，LTD的诱导， 双脉冲刺激依赖于N-甲基-D-天冬氨酸（NMDA） 受体激活和时间上重叠的抑制性输入， γ-氨基丁酸激活介导的突触后细胞靶点 A（GABAA）受体。 如果GABA能抑制较弱或不存在， 兴奋性激活，然后LTD无法发展。 第一个目标 目前的建议是测试GABA能的程度是否 双脉冲刺激期间的抑制控制了 成对脉冲串在体内诱导成年海马中的LTD。 的 诱导的LTD的维持和表达的基础机制 配对脉冲刺激目前尚不清楚。 的差别激活 蛋白激酶和磷酸酶通常被认为起着关键作用 调节双向活动依赖性突触可塑性。 的 因此，本建议的第二和第三个目的是审查 成年海马在体蛋白磷酸酶和蛋白 激酶活性，分别与LTD诱导 双脉冲刺激 拟议中的实验涉及一种罕见的 电生理学、药理学和生物化学的组合 技术，以获得深入的机制， 活动依赖的神经可塑性在完整的成人大脑。

DESCRIPTION (Investigator's abstract): Knowledge of the mechanisms that underlie activity-dependent neural plasticity is integral to understanding both normal and impaired memory function. The overall goal of the experiments proposed in this grant application is to study parameters critical for the induction and biochemical processes that underlie the maintenance and expression of long-term depression (LTD) of synaptic strength of glutamatergic synapses in the adult hippocampus in vivo. 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. A common paradigm for inducing LTD is the delivery of prolonged low-frequency stimulation to the afferent pathway. However, LTD induced in such a fashion has been found to occur only in in vitro preparations using tissue from young animals. We recently have demonstrated that repeated paired-pulse stimulation of the commissural pathway reliably induces robust LTD of the commissural input to CA1 pyramidal cells in the adult hippocampus in vivo. Subsequent experiments have revealed that the induction of LTD by paired-pulse stimulation is dependent on N-methyl-D-aspartate (NMDA) receptor activation and, temporally overlapping, inhibitory input to the postsynaptic cell target mediated by activation of gamma-amino-butyric acid A (GABAA) receptors. If GABAergic inhibition is weak or absent during excitatory activation, then LTD fails to develop. The first aim of the present proposal is to test whether or not the degree of GABAergic inhibition during paired-pulse stimulation controls the effectiveness of a train of paired pulses to induce LTD in the adult hippocampus in vivo. The mechanisms that underlie the maintenance and expression of LTD induced by paired-pulse stimulation currently are unknown. Differential activation of protein kinases and phosphatases commonly is thought to play a critical role in regulating bidirectional activity-dependent synaptic plasticity. The second and the third aim of the present proposal therefore is to examine in the adult hippocampus in vivo changes in protein phosphatase and protein kinase activity, respectively, in association with LTD induced by paired-pulse stimulation. The proposed experiments involve a rare combination of electrophysiological, pharmacological, and biochemical techniques to gain insight into the mechanisms that underlie activity-dependent neural plasticity in the intact adult brain.