COBRE: LSU:PROJ 4:CYCLOOXYGENASES IN NEURONAL SYNAPTIC PLASTICITY

COBRE：LSU：项目 4：神经元突触可塑性中的环加氧酶

• 批准号: 7719904
• 负责人: CHU S CHEN
• 金额: $ 15.57万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7719904
• 关键词: Action Potentials; Arachidonic Acids; Back; Chromosome Pairing; Computer Retrieval of Information on Scientific Projects Database; Coxibs; Data; Dendritic Spines; Dinoprostone; Enzymes; Epilepsy; Frequencies; Functional disorder; Funding; Goals; Grant; Hippocampus (Brain); Indium; Institution; Lipids; Localized; Long-Term Potentiation; Maintenance; Membrane; Neurodegenerative Disorders; Neurons; Phospholipase A2; Platelet Activating Factor; Probability; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Research; Research Personnel; Resources; Role; Seizures; Source; Stroke; Synapses; Synaptic plasticity; Testing; United States National Institutes of Health; cyclooxygenase 1; cyclooxygenase 2; hippocampal pyramidal neuron; inhibitor/antagonist; nervous system disorder; neuronal survival; postsynaptic

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of this project is to understand the significance of cyclooxygenase (COX) metabolites in the initiation and expression of long-term synaptic plasticity and neuronal survival. The bioactive lipids, arachidonic acid (AA) and platelet-activating factor (PAF), and phospholipase A2 (PLA2), the enzyme that generates them, have been implicated in expression or maintenance of long-term potentiation (LTP) in the hippocampus. However, little is known about the role of prostaglandins (PGs) in synaptic plasticity. PGs are synthesized from AA via COX. Two COX isoforms, COX-1 and COX-2, have been identified. Neuronal COX-2 expression is rapidly induced by ischemic, seizures and NMDA-dependent synaptic activity. Further evidence shows that COX-2 is expressed in postsynaptic dendritic spines where active synapses are present. Our preliminary data indicate that selective COX-2 inhibitors, but not COX-1 inhibitors, reduce membrane excitability and high-frequency stimulation (HFS)- induced LTP in hippocampal neurons and that application of PGE2 rescues COX-2 inhibitor-induced suppressions of LTP induction and membrane excitability. This information implicates PGs synthesized by COX-2 for an important role in processing and storage of synaptic information. Recent evidence indicates that the back-propagating dendritic action potential is a critical element in the induction of long-term synaptic plasticity in hippocampal pyramidal neurons. Thus, we hypothesize that synaptic activity-dependent synthesis of PGs catalyzed by COX-2 regulates the probability of LTP induction by modifying dendritic excitability of hippocampal pyramidal neurons. Four specific aims are proposed to test predictions of this hypothesis,: 1) synaptic activity-dependent synthesis of PG(s) by COX-2 increases dendritic excitability; 2) postsynaptic synthesis of PGs by COX-2 is activity-dependent; 3) localized application of AA and PG(s) will mimic the effect of coincident synaptic activity; and 4) COX-2 synthesized PG(s) regulates membrane excitability and long-term synaptic activity in hippocampal pyramidal neurons. The proposed project will further our understanding of hippocampal synaptic plasticity and will also contribute towards the understanding of the pathophysiology of neurological disorders such as epilepsy, stroke, and neurodegenerative diseases.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目的长期目标是了解环氧合酶（考克斯）代谢产物在长时程突触可塑性和神经元存活的启动和表达中的意义。 生物活性脂质，花生四烯酸（AA）和血小板活化因子（PAF），和磷脂酶A2（PLA 2），产生它们的酶，已被牵连在表达或维持的长时程增强（LTP）在海马。 然而，鲜为人知的是，在突触可塑性中的作用，前列腺素（PGs）。 PG由AA通过考克斯合成。 已经鉴定了两种考克斯同种型，考克斯-1和考克斯-2。 神经元考克斯-2的表达被缺血、癫痫发作和NMDA依赖性突触活动迅速诱导。 进一步的证据表明，考克斯-2在突触后树突棘中表达，在那里存在活跃的突触。 我们的初步数据表明，选择性的考克斯-2抑制剂，但不是考克斯-1抑制剂，降低膜兴奋性和高频刺激（HFS）诱导的LTP在海马神经元和前列腺素E2的应用救援考克斯-2抑制剂诱导的抑制LTP的诱导和膜兴奋性。 这些信息暗示由考克斯-2合成的PG在突触信息的加工和储存中起重要作用。 最近的证据表明，反向传播树突状细胞动作电位是诱导海马锥体神经元长时程突触可塑性的关键因素。 因此，我们推测，突触活性依赖性合成的PGs催化的考克斯-2调节LTP诱导的可能性，通过修改树突兴奋性的海马锥体神经元。 为了验证这一假说，我们提出了四个具体的目标：1）突触活动依赖性的考克斯-2合成PG（s）增加树突兴奋性，2）突触后考克斯-2合成PG是活动依赖性的，3）AA和PG（s）的局部应用将模拟突触活动一致的效果，4）突触后突触后PG（s）的合成与突触活动一致。考克斯-2合成的PG（s）调节海马锥体神经元的膜兴奋性和长时程突触活动。 拟议的项目将进一步我们的海马突触可塑性的理解，也将有助于对神经系统疾病，如癫痫，中风和神经退行性疾病的病理生理学的理解。