Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice
Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice
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DOI：
10.1038/sj.npp.1301640
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发表时间：
2008-09-01
影响因子：
7.6
通讯作者：
Knepel, Willhart
中科院分区：
文献类型：
--
作者：
Boeer, Ulrike;Cierny, Irmgard;Knepel, Willhart
情绪稳定剂锂的分子作用机制被认为涉及导致神经元适应的基因表达变化。转录因子CREB（cAMP反应元件结合蛋白）调节许多基因的表达，并与重要的脑功能和心因性药物的作用有关。在这里，我们研究了锂对cAMP反应元件（CRE）/CREB介导的基因转录在大脑中的影响，使用转基因报告小鼠，表达荧光素酶报告基因的控制下的四个副本的大鼠生长抑素基因启动子CRE。慢性（21天），但不是急性（24小时）治疗锂（7.5 mmol/kg）显着降低CRE/CREB-定向基因表达海马，皮质，下丘脑，纹状体60- 70%，同样减少CREB磷酸化。由于双相情感障碍也被认为是一种应激相关的障碍，因此在接受慢性心理社会应激范式的小鼠中测定了锂的作用。如前所述，25天的应激显著增加了几个大脑区域中CRE/CREB指导的基因表达100- 150%。用锂处理应激小鼠，几乎所有脑区的应激诱导的CRE/CREB定向基因表达都降低到对照水平，同样也降低了CREB磷酸化。慢性锂处理诱导β-连环蛋白积累和降低cAMP水平，表明锂对糖原合成酶激酶3和腺苷酸环化酶/蛋白激酶A信号级联的抑制作用，这是已知的调节CREB活性。我们在这里第一次表明，锂调节CRE/CREB定向基因转录在体内，并建议CREB作为一个假定的调解人的神经元适应后，慢性锂处理。
The molecular mechanism of action of the mood stabilizer lithium is assumed to involve changes in gene expression leading to neuronal adaptation. The transcription factor CREB (cAMP-responsive element binding protein) regulates the expression of many genes and has been implicated in important brain functions and the action of psychogenic agents. We here investigated the effect of lithium on cAMP-responsive element (CRE)/CREB-mediated gene transcription in the brain, using transgenic reporter mice that express the luciferase reporter gene under the control of four copies of the rat somatostatin gene promoter CRE. Chronic ( 21 days) but not acute ( 24 h) treatment with lithium (7.5 mmol/kg) significantly decreased CRE/CREB-directed gene expression in hippocampus, cortex, hypothalamus, and striatum to 60-70%, and likewise reduced CREB phosphorylation. As bipolar disorder is also considered as a stress-related disorder, the effect of lithium was determined in mice submitted to a paradigm for chronic psychosocial stress. As shown before, stress for 25 days significantly increased CRE/CREB-directed gene expression in several brain regions by 100-150%. Treatment of stressed mice with lithium decreased stress-induced CRE/CREB-directed gene expression to control levels in nearly all brain regions and likewise reduced CREB phosphorylation. Chronic lithium treatment induced beta-catenin accumulation and decreased cAMP levels, indicating an inhibitory effect of lithium on glycogen synthase kinase 3 and the adenylate cyclase/protein kinase A signalling cascade, which are known to modulate CREB activity. We here for the first time show that lithium regulates CRE/CREB-directed gene transcription in vivo and suggest CREB as a putative mediator of the neuronal adaptation after chronic lithium treatment.