Modulation of Hippocampal Synaptic Plasticity

描述（由申请人提供）：N-甲基-D-天冬氨酸（NMDAR）在信息处理和作为学习和记忆基础的突触可塑性中起关键作用。根据其激活模式，NMDAR可以促进长时程增强（LTP）或长时程突触抑制（LTD），这是哺乳动物大脑中记忆机制的两种主要候选者。当过度激活时，NMDAR也会导致几种形式的神经变性。重要的是，似乎NMDAR的不同亚类和不同的信号通路有助于突触可塑性和神经变性。我们已经观察到，在突触可塑性和神经变性之间也存在中间状态，其中NMDAR激活不产生突触反应或神经元损伤的变化，但抑制产生LTP的能力。这种NMDAR介导的LTP抑制在NMDAR的低水平激活、某些突触刺激模式和暴露于亚致死应激条件（短暂缺氧、低葡萄糖和氨）下观察到。由于突触可塑性似乎在记忆处理中起作用，这种NMDAR介导的LTP抑制对于理解神经精神障碍中伴随NMDAR过早激活的认知缺陷可能是重要的。在这个提议中，我们将通过检查有助于这种形式的突触调制的因素来扩展我们对NMDAR LTP抑制的初步工作。我们研究的目的是1。确定NMDAR亚类在LTP抑制中的作用; 2.确定有助于NMDAR介导的LTP抑制的细胞内途径，重点是表明NMDAR的特定分子亚类与不同类别的细胞内信使偶联的证据;和3.确定NMDAR-LTP抑制是否代表一种代谢应激形式，重点是进行初步研究，表明在NMDAR过早激活后给药时，替代能量底物（如丙酮酸）可克服LTP抑制。这些研究将在大鼠海马切片的CA 1区进行，该区域已知对记忆处理很重要。我们研究的长期目标是确定神经精神疾病患者保持和恢复突触功能的方法。

DESCRIPTION (provided by applicant): N-methyl-D-aspartate (NMDARs) play critical roles in information processing and in the synaptic plasticity that underlies learning and memory. Depending upon their pattern of activation, NMDARs can promote long- term potentiation (LTP) or long-term synaptic depression (LTD), two leading candidates for memory mechanisms in the mammalian brain. When activated excessively, NMDARs also cause several forms of neurodegeneration. Importantly, it appears that different subclasses of NMDARs and different signaling pathways contribute to synaptic plasticity and neurodegeneration. We have observed that there are also conditions, intermediate between synaptic plasticity and neurodegeneration, in which NMDAR activation produces no change in synaptic responses or neuronal injury but inhibits the ability to generate LTP. This NMDAR-mediated LTP inhibition is observed with low level activation of NMDARs, certain patterns of synaptic stimulation and exposure to sub-lethal stressful conditions (brief hypoxia, low glucose and ammonia). Because of the role that synaptic plasticity appears to play in memory processing, this NMDAR- mediated LTP inhibition may be important for understanding cognitive defects that accompany untimely NMDAR activation in neuropsychiatric disorders. In this proposal, we will extend our initial work on NMDAR LTP inhibition by examining factors that contribute to this form of synaptic modulation. The aims of our studies are 1. To determine the role of subclasses of NMDARs in LTP inhibition; 2. To determine intracellular pathways contributing to NMDAR-mediated LTP inhibition with emphasis on evidence indicating that specific molecular subclasses of NMDARs couple to different classes of intracellular messengers; and 3. To determine whether NMDAR-LTP inhibition represents a form of metabolic stress with emphasis on pursuing preliminary studies indicating that alternative energy substrates such as pyruvate overcome the LTP inhibition when administered following untimely NMDAR activation. These studies will be conducted in the CA1 region of rat hippocampal slices, an area known to be important for memory processing. The long-term goal of our studies is to identify ways to preserve and restore synaptic function in individuals with neuropsychiatric disorders.