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（由申请人提供）：n -甲基- d -天冬氨酸（NMDARs）在信息处理和突触可塑性中发挥关键作用，这是学习和记忆的基础。根据它们的激活模式，NMDARs可以促进长时程增强（LTP）或长时程突触抑制（LTD），这是哺乳动物大脑记忆机制的两种主要候选。当过度激活时，NMDARs还会引起几种形式的神经变性。重要的是，NMDARs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退行性变。我们观察到，在突触可塑性和神经退行性之间也存在一些条件，其中NMDAR激活不会改变突触反应或神经元损伤，但会抑制产生LTP的能力。这种nmdar介导的LTP抑制是在低水平的nmdar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、低糖和低氨）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抑制可能对理解神经精神疾病中伴随NMDAR过早激活的认知缺陷很重要。在本提案中，我们将通过研究促成这种形式的突触调节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NMDARs亚类在LTP抑制中的作用；2. 确定参与nmdar介导的LTP抑制的细胞内通路，重点关注NMDARs的特定分子亚类与不同类型的细胞内信使偶联的证据；和3。为了确定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过早激活后给予替代能源底物（如丙酮酸）克服LTP抑制。这些研究将在大鼠海马切片的CA1区域进行，这是一个已知对记忆处理很重要的区域。我们研究的长期目标是确定保存和恢复神经精神疾病患者突触功能的方法。