Modulation of Hippocampal Synaptic Plasticity

海马突触可塑性的调节

• 批准号: 7252752
• 负责人: CHARLES F ZORUMSKI
• 金额: $ 32.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252752
• 关键词: Adverse effects; Ammonia; Area; Biochemical; Brain; Calcium; Cessation of life; Chromosome Pairing; Class; Cognitive; Computer information processing; Condition; Data; Defect; Disease; Event; Exposure to; Functional disorder; Glucose; Glutamates; Goals; Hippocampus (Brain); Hypoxia; Individual; Isoxazoles; Laboratories; Learning; Link; Long-Term Depression; Long-Term Potentiation; Magnesium; Mediating; Memory; Mental Depression; Metabolic stress; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neuronal Injury; Neurons; Pathway interactions; Pattern; Perfusion; Play; Propionic Acids; Propionic acid; Pyruvate; Pyruvates; Rattus; Receptor Activation; Role; Signal Pathway; Slice; Solutions; Synapses; Synaptic plasticity; Work; base; memory process; neuronal growth; neuropsychiatry; postsynaptic; receptor; receptor coupling; response; synaptic function; transmission process

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.

描述（由申请人提供）：N-甲基-D-天冬氨酸（NMDAR）在信息处理以及学习和记忆基础的突触可塑性中发挥着关键作用。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个主要候选者。当过度激活时，NMDAR 还会引起多种形式的神经变性。重要的是，NMDAR 的不同亚类和不同的信号通路似乎有助于突触可塑性和神经变性。我们观察到，也存在介于突触可塑性和神经变性之间的情况，其中 NMDAR 激活不会导致突触反应或神经元损伤发生变化，但会抑制产生 LTP 的能力。这种 NMDAR 介导的 LTP 抑制是在 NMDAR 的低水平激活、某些突触刺激模式以及暴露于亚致死应激条件（短暂缺氧、低葡萄糖和氨）下观察到的。由于突触可塑性似乎在记忆处理中发挥着重要作用，这种 NMDAR 介导的 LTP 抑制可能对于理解神经精神疾病中伴随着 NMDAR 过早激活的认知缺陷非常重要。在本提案中，我们将通过检查有助于这种形式的突触调节的因素来扩展我们在 NMDAR LTP 抑制方面的初步工作。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； 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 不合时宜激活后施用替代能源底物（如丙酮酸）可克服 LTP 抑制。这些研究将在大鼠海马切片的 CA1 区域进行，该区域已知对记忆处理很重要。我们研究的长期目标是找到保护和恢复神经精神疾病患者突触功能的方法。