MODULATION OF HIPPOCAMPAL SYNAPTIC PLASTICITY

描述(申请人提供)：N-甲基-D-天冬氨酸受体(NMDAR)在信息处理和作为学习和学习基础的突触可塑性中发挥关键作用 记忆。根据激活模式的不同，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NMDAR过度激活时，也会导致几种形式的神经退化。我们观察到，在某些情况下，NMDAR的激活不会改变突触反应或神经元损伤，但会损害产生LTP的能力。这种NMDAR介导的LTP抑制是在NMDAR低水平激活、某些突触刺激模式和暴露于亚致死应激条件(短暂缺氧和低糖)的情况下观察到的。由于突触可塑性在记忆加工中所起的作用，这种NMDAR介导的LTP抑制对于理解神经精神障碍中伴随着NMDAR过早激活的认知缺陷可能是重要的。在最近的研究中，我们发现低水平的NMDAR激活促进了海马锥体神经元中GABA增强型神经类固醇的产生，这些神经类固醇在LTP抑制中起着关键作用。在这项提案中，我们将通过以下三个目标来扩展我们对NMDAR LTP抑制的研究：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参与LTP调节；2.确定NMDAR诱导的神经类固醇产生的信号机制；以及3.确定NMDA和神经类固醇对GABA能抑制的影响及其机制。这些研究将在大鼠海马片的CA1区进行，该区域被认为是记忆处理的重要区域。我们的长期目标是找到保存和恢复神经精神疾病患者突触功能的方法。 公共卫生相关性：精神障碍涉及认知、情感和动机基础上的神经回路功能障碍。尽管对这些疾病的生物学了解甚少，但海马体已经成为几种疾病的主要枢纽，并在涉及心理功能和陈述性记忆形成的大脑系统中发挥关键作用。在这些研究中，我们将研究在应激条件下导致海马体功能障碍的机制，包括神经类固醇的作用。这些研究有可能为海马体在神经精神疾病中的作用提供新的线索，并确定新的治疗方法。

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. PUBLIC HEALTH RELEVANCE: Psychiatric disorders involve dysfunction in neural circuits underlying cognition, emotion and motivation. Although the biology of these disorders is poorly understood, the hippocampus has emerged as a major hub in several disorders and plays a critical role in brain systems involved in mental function and declarative memory formation. In these studies, we will examine mechanisms underlying hippocampal dysfunction in stressful conditions, including the role of neurosteroids. These studies have potential to shed new light on the role of the hippocampus in neuropsychiatric illnesses and to identify novel approaches to treatment.