Modulation of Hippocampal Synaptic Plasticity

海马突触可塑性的调节

基本信息

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
项目类别：
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

项目摘要

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）在信息处理以及基于学习和记忆的突触可塑性中起关键作用。根据其激活模式，NMDAR可以促进长期增强（LTP）或长期突触抑郁症（LTD），这是两个领先的哺乳动物大脑记忆机制的主要候选者。当过度激活时，NMDAR还会引起几种形式的神经变性。重要的是，似乎NMDAR的不同亚类和不同的信号通路有助于突触可塑性和神经变性。我们已经观察到，在突触可塑性和神经退行性之间也存在一些条件，其中NMDAR激活不会产生突触反应或神经元损伤的变化，但会抑制产生LTP的能力。该NMDAR介导的LTP抑制是通过NMDAR的低水平激活，某些突触刺激的模式以及暴露于亚致死性胁迫条件（短暂缺氧，低葡萄糖和氨）的情况。由于突触可塑性在记忆加工中似乎起着作用，因此这种NMDAR介导的LTP抑制作用对于理解伴随神经精神疾病中不合时宜的NMDAR激活的认知缺陷可能很重要。在此提案中，我们将通过检查有助于这种突触调节形式的因素来扩展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。确定有助于NMDAR介导的LTP抑制的细胞内途径，重点是证据表明NMDAR的特定分子亚类夫妇夫妇与不同类别的细胞内信使相对。 3。确定NMDAR-LTP抑制是否代表了一种代谢应激的形式，重点是追求初步研究，表明诸如丙酮酸等替代能量底物在不合时宜的NMDAR激活后给予LTP抑制。这些研究将在大鼠海马切片的CA1区域进行，该区域已知对于记忆加工很重要。我们研究的长期目标是确定神经精神疾病患者中保留和恢复突触功能的方法。