MODULATION OF HIPPOCAMPAL SYNAPTIC PLASTICITY

描述（由申请人提供）：N-甲基-D-天冬氨酸受体（NMDAR）在信息处理和突触可塑性中起关键作用，突触可塑性是学习和记忆的基础。 记忆根据激活模式，NMDAR可以促进长时程增强（LTP）或长时程突触抑制（LTD），这是突触记忆机制的两个主要候选者。然而，当过度激活时，NMDAR也会导致几种形式的神经变性。我们还观察到，在某些情况下，NMDAR激活不会引起突触反应或神经元损伤的变化，但会损害产生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（短暂缺氧和低葡萄糖）下观察到。由于突触可塑性在记忆处理中的作用，这种NMDAR介导的LTP抑制对于理解神经精神疾病中伴随NMDAR过早激活的认知缺陷可能是重要的。近年来的研究发现，低水平的NMDAR激活可促进海马锥体神经元产生增强GABA的神经甾体，这些神经甾体在LTP抑制中起关键作用。在这个提议中，我们将通过追求三个目标来扩展我们在NMDAR LTP抑制方面的工作：1.确定NMDAR激活促进神经类固醇产生的条件以及类固醇如何有助于LTP调节; 2.确定NMDAR诱导的神经类固醇产生的信号传导机制;和3.探讨NMDA和神经甾体对GABA能抑制的影响及其机制。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。我们的长期目标是确定在患有神经精神疾病的个体中保持和恢复突触功能的方法。

DESCRIPTION (provided by applicant): N-methyl-D-aspartate receptors (NMDARs) play critical roles in information processing and in the synaptic plasticity that underlies learning and memory. Depending upon the pattern of activation, NMDARs can promote long-term potentiation (LTP) or long-term synaptic depression (LTD), two leading candidates for synaptic memory mechanisms. When activated excessively, however, NMDARs can also cause several forms of neurodegeneration. We have observed that there are also conditions in which NMDAR activation produces no change in synaptic responses or neuronal injury, but impairs 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 and low glucose). Because of the role that synaptic plasticity plays in memory processing, this NMDAR-mediated LTP inhibition may be important for understanding the cognitive defects that accompany untimely NMDAR activation in neuropsychiatric disorders. In recent studies, we found that low level NMDAR activation promotes the production of GABA-enhancing neurosteroids in hippocampal pyramidal neurons and these neurosteroids play a key role in LTP inhibition. In this proposal, we will extend our work on NMDAR LTP inhibition by pursuing three aims: 1. To determine conditions under which NMDAR activation promotes neurosteroid production and how steroids contribute to LTP modulation; 2. To determine signaling mechanisms underlying NMDAR-induced neurosteroid production; and 3. To determine the effects of NMDA and neurosteroids on GABAergic inhibition and the mechanisms underlying these effects. These studies will be conducted in the CA1 region of rat hippocampal slices, an area known to be important for memory processing. Our long-term goal is to identify ways to preserve and restore synaptic function in individuals with neuropsychiatric illnesses.