β-catenin overexpression in the mouse brain phenocopies lithium-sensitive Behaviors
β-catenin overexpression in the mouse brain phenocopies lithium-sensitive Behaviors
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DOI：
10.1038/sj.npp.1301338
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发表时间：
2007-10-01
影响因子：
7.6
通讯作者：
Manji, Husseini K.
中科院分区：
文献类型：
--
作者：
Gould, Todd D.;Einat, Haim;Manji, Husseini K.
锂在治疗浓度下抑制糖原合成酶激酶3 (GSK-3)；然而，尚不清楚这种抑制及其对特定信号通路的下游作用是否与双相情感障碍和抑郁症的治疗有关。GSK-3的靶标之一是转录因子-连环蛋白。正常活性GSK-3磷酸化-连环蛋白，导致其降解。因此抑制GSK3会增加-连环蛋白。我们利用转基因小鼠来研究CNS β -连环蛋白过表达的行为后果。过度表达β -连环蛋白的转基因小鼠表现出与服用锂后相似的行为变化，包括在强迫游泳试验（FST）中减少不动时间。此外，我们表明，尽管锂的急性给药和β -catenin转基因的过度表达抑制了d-安非他明诱导的过度运动，但锂和β -catenin转基因都不能阻止d-安非他明诱导的致敏，通过运动活动来测量。锂处理的小鼠和β -连环蛋白小鼠在多次给药后对d-安非他明的反应都有所提高，尽管在整个致敏过程中绝对运动的差异保持不变。急性锂离子和β -连环蛋白过表达对d-安非他明诱导的刻板行为都没有影响。在这项研究中，β -catenin转基因小鼠表现出与锂处理小鼠相同的行为，这与锂在这些模型中的行为影响是通过其直接抑制GSK-3和随之而来的β -catenin增加而介导的假设一致。通过将锂对行为的影响与β -连环蛋白水平联系起来，这些数据表明，增加β -连环蛋白可能是一种治疗情绪障碍的新策略。
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 GSK3 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.