CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticus
CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticus
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DOI：
10.1016/j.nbd.2006.08.015
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发表时间：
2007-01-01
影响因子：
6.1
通讯作者：
Obrietan, Karl
中科院分区：
文献类型：
--
作者：
Lee, Boyoung;Dziema, Heather;Obrietan, Karl
癫痫持续状态（SE）触发神经元死亡、反应性胶质增生和突触回路重塑，从而导致CNS生理学的深刻病理改变。这些过程，部分，调节细胞毒性和细胞保护基因的快速上调。一种可能将SE与CNS生理学中的转录依赖性改变偶联的途径是CREB（cAMP反应元件结合蛋白）/CRE（cAMP反应元件）级联。在这里，我们利用毛果芸香碱模型的SE小鼠品系转基因的CREB-报告构建体（β-半乳糖苷酶）开始，以表征癫痫发作活动如何调节激活状态的CREB/CRE通路的神经胶质细胞和海马神经元。SE触发了快速（4-8小时后SE），但短暂的增加，在神经元亚层的CREE介导的基因表达。与神经元相反，SE诱导反应性星形胶质细胞和小胶质细胞中CRE介导的转录持续增加（长达20天）。CRE介导的基因表达与促炎酶环氧合酶-2（考克斯-2）的表达相关。为了研究CREB在SE诱导的考克斯-2表达中的作用，我们产生了表达A-CREB的转基因小鼠品系，A-CREB是CREB依赖性转录的有效阻遏物。在这些动物中，SE刺激考克斯-2表达的能力明显减弱，表明CREB是SE诱导的考克斯-2表达的关键中间体。总的来说，这些数据表明，SE触发CREB介导的基因表达的两个波，在神经元中的瞬时波和反应性胶质细胞中的持久波，并且CREB将SE与考克斯-2表达偶联。(c)2006年爱思唯尔公司All rights reserved.
Status epilepticus (SE) triggers neuronal death, reactive gliosis and remodeling of synaptic circuitry, thus leading to profound pathological alterations in CNS physiology. These processes are, in part, regulated by the rapid upregulation of both cytotoxic and cytoprotective genes. One pathway that may couple SE to transcriptionally dependent alterations in CNS physiology is the CREB (cAMP response element-binding protein)/CRE (cAMP response element) cascade. Here, we utilized the pilocarpine model of SE on a mouse strain transgenic for a CRE-reporter construct (beta-galactosidase) to begin to characterize how seizure activity regulates the activation state of the CREB/CRE pathway in both glia and neurons of the hippocampus. SE triggered a rapid (4-8 h post-SE) but transient increase in CRE-mediated gene expression in the neuronal sublayers. In contrast to neurons, SE induced a lasting increase (up to 20 days) in CRE-mediated transcription in both reactive astrocytes and microglia. CRE-mediated gene expression correlated with expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2). To examine the role of CREB in SE-induced COX-2 expression, we generated a transgenic mouse strain that expresses A-CREB, a potent repressor of CREB-dependent transcription. In these animals, the capacity of SE to stimulate COX-2 expression was markedly attenuated, indicating that CREB is a key intermediate in SE-induced COX-2 expression. Collectively these data show that SE triggers two waves of CREB-mediated gene expression, a transient wave in neurons and a long-lasting wave in reactive glial cells, and that CREB couples SE to COX-2 expression. (c) 2006 Elsevier Inc. All rights reserved.