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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本项目的长期目标是了解环氧化酶（COX）代谢物在突触长期可塑性的启动和表达以及神经元存活中的意义。生物活性脂质，花生四烯酸（AA）和血小板活化因子（PAF），以及产生它们的酶磷脂酶A2 (PLA2)，与海马中长期增强（LTP）的表达或维持有关。然而，人们对前列腺素在突触可塑性中的作用知之甚少。PGs是由AA经COX合成的。已鉴定出COX-1和COX-2两种COX亚型。神经元COX-2的表达可被缺血、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，COX-2在突触后树突棘中表达，那里存在活跃的突触。我们的初步数据表明，选择性COX-2抑制剂，而不是COX-1抑制剂，降低了海马神经元的膜兴奋性和高频刺激（HFS）诱导的LTP， PGE2的应用挽救了COX-2抑制剂诱导的LTP诱导和膜兴奋性的抑制。这一信息表明COX-2合成的pg在突触信息的处理和存储中起着重要作用。最近的证据表明，反向传播的树突动作电位是诱导海马锥体神经元长期突触可塑性的关键因素。因此，我们假设COX-2催化的PGs的突触活动依赖性合成通过改变海马锥体神经元的树突兴奋性来调节LTP诱导的可能性。提出了四个具体目标来验证这一假设的预测：1)突触活动依赖于COX-2合成的PG(s)增加了树突的兴奋性；2) COX-2突触后合成pg具有活性依赖性；3)局部应用AA和PG(s)可模拟同步突触活动的效果；4) COX-2合成的PG(s)调节海马锥体神经元的膜兴奋性和长期突触活性。该项目将进一步加深我们对海马突触可塑性的理解，也将有助于理解神经系统疾病（如癫痫、中风和神经退行性疾病）的病理生理学。

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.