Gould Todd D, Einat Haim, O'Donnell Kelley C, Picchini Alyssa M, Schloesser Robert J, Manji Husseini K
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-3711, USA.
Neuropsychopharmacology. 2007 Oct;32(10):2173-83. doi: 10.1038/sj.npp.1301338. Epub 2007 Feb 14.
Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is unclear if this inhibition and its downstream effects on specific signaling pathways are relevant to the treatment of bipolar disorder and depression. One of the targets of GSK-3 is the transcription factor beta-catenin. Normally active GSK-3 phosphorylates beta-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases beta-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS beta-catenin overexpression. Transgenic mice overexpressing beta-catenin demonstrated behavioral changes similar to those observed following the administration of lithium, including decreased immobility time in the forced swim test (FST). Further, we show that although acute administration of lithium and overexpression of the beta-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the beta-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithium-treated and beta-catenin mice had an elevated response to d-amphetamine following multiple administrations of the stimulant, though the difference in absolute locomotion was maintained throughout the sensitization time-course. Neither acute lithium nor beta-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which beta-catenin transgenic mice exhibited behaviors identical to those observed in lithium-treated mice, are consistent with the hypothesis that the behavioral effects of lithium in these models are mediated through its direct inhibition of GSK-3 and the consequent increase in beta-catenin. By associating the behavioral effects of lithium with beta-catenin levels, these data suggest that increasing beta-catenin might be a novel therapeutic strategy for mood disorders.
锂在治疗浓度下可抑制糖原合酶激酶-3（GSK-3）；然而，尚不清楚这种抑制作用及其对特定信号通路的下游效应是否与双相情感障碍和抑郁症的治疗相关。GSK-3的一个靶点是转录因子β-连环蛋白。正常情况下，活性GSK-3会使β-连环蛋白磷酸化，导致其降解。因此，抑制GSK-3会增加β-连环蛋白的含量。我们利用转基因小鼠来研究中枢神经系统中β-连环蛋白过表达的行为后果。过表达β-连环蛋白的转基因小鼠表现出与给予锂后观察到的行为变化相似，包括在强迫游泳试验（FST）中不动时间减少。此外，我们发现，尽管急性给予锂和β-连环蛋白转基因过表达可抑制右旋苯丙胺诱导的运动亢进，但锂和β-连环蛋白转基因均不能预防右旋苯丙胺诱导的致敏作用，这通过运动活性来衡量。在多次给予兴奋剂后，锂处理组和β-连环蛋白小鼠对右旋苯丙胺的反应均增强，尽管在整个致敏时间过程中绝对运动的差异一直存在。急性给予锂或β-连环蛋白过表达对右旋苯丙胺诱导的刻板行为均无影响。在这项研究中，β-连环蛋白转基因小鼠表现出与锂处理小鼠相同的行为，其结果与以下假设一致：在这些模型中，锂的行为效应是通过其对GSK-3的直接抑制以及随之而来的β-连环蛋白增加来介导的。通过将锂的行为效应与β-连环蛋白水平联系起来，这些数据表明增加β-连环蛋白可能是治疗情绪障碍的一种新策略。
