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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的长期目标是了解环氧合酶(COX)代谢产物在启动和表达长期突触可塑性和神经元存活中的意义。生物活性脂类花生四烯酸(AA)和血小板激活因子(PAF)以及产生它们的磷脂酶A2(PLA2)与海马长时程增强(LTP)的表达或维持有关。然而，对前列腺素(PGs)在突触可塑性中的作用知之甚少。PGS是由AA通过COX合成的。目前已鉴定出COX-1和COX-2两种亚型。神经元COX-2的表达受缺血、癫痫发作和NMDA依赖的突触活动的快速诱导。进一步的证据表明，COX-2在突触活跃的突触后树突棘中表达。我们的初步数据表明，选择性的COX-2抑制剂，而不是COX-1抑制剂，可以降低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时程突触可塑性的关键因素。因此，我们假设COX-2催化的突触活性依赖的PG的合成通过改变海马锥体神经元的树突兴奋性来调节LTP的诱导概率。为了验证这一假说的预测，我们提出了四个特定的目标：1)由COX-2合成的PG(S)依赖突触活性增加树突状细胞的兴奋性；2)由COX-2合成的PG是活性依赖的；3)局部应用AA和PG(S)将模拟一致的突触活动的效应；以及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区突触可塑性的理解，也将有助于理解癫痫、中风和神经退行性疾病等神经疾病的病理生理学。

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.