Modulation of Hippocampal Synaptic Plasticity

海马突触可塑性的调节

• 批准号: 7798640
• 负责人: CHARLES F ZORUMSKI
• 金额: $ 32.3万
• 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/7798640
• 关键词: Adverse effects; Ammonia; Area; Biochemical; Brain; Calcium; Cessation of life; Cognitive; 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; Pyruvate; Pyruvates; Rattus; Receptor Activation; Role; Signal Pathway; Slice; Solutions; Synapses; Synaptic plasticity; Work; base; information processing; 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(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发挥关键作用。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)，这是哺乳动物大脑中记忆机制的两个主要候选因素。当NMDAR过度激活时，也会导致几种形式的神经退化。重要的是，NMDAR的不同亚类和不同的信号通路似乎与突触可塑性和神经退行性变有关。我们观察到，在突触可塑性和神经退行性变之间的条件下，NMDAR激活不会改变突触反应或神经元损伤，但抑制产生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、低糖和氨)的情况下观察到的。由于突触可塑性似乎在记忆加工中发挥作用，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。在这项提案中，我们将通过研究与这种形式的突触调制有关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NMDAR介导的LTP抑制的细胞内途径，重点是有证据表明特定的NMDAR亚类与不同类型的细胞内信使偶联；以及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，表明替代能源底物，如丙酮酸，在NMDAR异常激活后给予时，可以克服LTP抑制。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。我们研究的长期目标是确定保存和恢复神经精神障碍患者突触功能的方法。