Misztal Katarzyna, Brozko Nikola, Nagalski Andrzej, Szewczyk Lukasz M, Krolak Marta, Brzozowska Katarzyna, Kuznicki Jacek, Wisniewska Marta B
International Institute of Molecular and Cell Biology, Laboratory of Neurodegeneration, Warsaw, Poland.
International Institute of Molecular and Cell Biology, Laboratory of Neurodegeneration, Warsaw, Poland; University of Warsaw, Centre of New Technologies, Laboratory of Molecular Neurobiology, Poland; Postgraduate School of Molecular Medicine, Warsaw, Poland.
Neuropharmacology. 2017 Feb;113(Pt A):490-501. doi: 10.1016/j.neuropharm.2016.10.027. Epub 2016 Oct 25.
The mechanism of lithium's therapeutic action remains obscure, hindering the discovery of safer treatments for bipolar disorder. Lithium can act as an inhibitor of the kinase GSK3α/β, which in turn negatively regulates β-catenin, a co-activator of LEF1/TCF transcription factors. However, unclear is whether therapeutic levels of lithium activate β-catenin in the brain, and whether this activation could have a therapeutic significance. To address this issue we chronically treated mice with lithium. Although the level of non-phospho-β-catenin increased in all of the brain areas examined, β-catenin translocated into cellular nuclei only in the thalamus. Similar results were obtained when thalamic and cortical neurons were treated with a therapeutically relevant concentration of lithium in vitro. We tested if TCF7L2, a member of LEF1/TCF family that is highly expressed in the thalamus, facilitated the activation of β-catenin. Silencing of Tcf7l2 in thalamic neurons prevented β-catenin from entering the nucleus, even when the cells were treated with lithium. Conversely, when Tcf7l2 was ectopically expressed in cortical neurons, β-catenin shifted to the nucleus, and lithium augmented this process. Lastly, we silenced tcf7l2 in zebrafish and exposed them to lithium for 3 days, to evaluate whether TCF7L2 is involved in the behavioral response. Lithium decreased the dark-induced activity of control zebrafish, whereas the activity of zebrafish with tcf7l2 knockdown was unaltered. We conclude that therapeutic levels of lithium activate β-catenin selectively in thalamic neurons. This effect is determined by the presence of TCF7L2, and potentially contributes to the therapeutic response.
锂的治疗作用机制仍不清楚，这阻碍了双相情感障碍更安全治疗方法的发现。锂可作为激酶GSK3α/β的抑制剂，进而负向调节β-连环蛋白，β-连环蛋白是LEF1/TCF转录因子的共激活因子。然而，尚不清楚锂的治疗水平是否能在大脑中激活β-连环蛋白，以及这种激活是否具有治疗意义。为解决这个问题，我们用锂对小鼠进行了长期治疗。尽管在所检查的所有脑区中，非磷酸化β-连环蛋白的水平都有所增加，但β-连环蛋白仅在丘脑中转移到细胞核中。当用治疗相关浓度的锂在体外处理丘脑和皮质神经元时，也得到了类似的结果。我们测试了LEF1/TCF家族中在丘脑中高表达的成员TCF7L2是否促进β-连环蛋白的激活。丘脑神经元中Tcf7l2的沉默阻止了β-连环蛋白进入细胞核，即使细胞用锂处理也是如此。相反，当Tcf7l2在皮质神经元中异位表达时，β-连环蛋白转移到细胞核中，锂增强了这一过程。最后，我们在斑马鱼中沉默tcf7l2，并使其暴露于锂中3天，以评估TCF7L2是否参与行为反应。锂降低了对照斑马鱼的暗诱导活动，而敲低tcf7l2的斑马鱼的活动未改变。我们得出结论，锂的治疗水平在丘脑神经元中选择性地激活β-连环蛋白。这种效应由TCF7L2的存在决定，并可能有助于治疗反应。
