التفاصيل البيبلوغرافية
| العنوان: |
TCF7L2 mediates the cellular and behavioral response to chronic lithium treatment in animal models. |
| المؤلفون: |
Misztal, Katarzyna1, Brozko, Nikola1,2,3, Nagalski, Andrzej1,2, Szewczyk, Lukasz M.1,3, Krolak, Marta4, Brzozowska, Katarzyna1,2,3, Kuznicki, Jacek1, Wisniewska, Marta B.1,2 m.wisniewska@uw.edu.pl |
| المصدر: |
Neuropharmacology. Feb2017 Part A, Vol. 113, p490-501. 12p. |
| مصطلحات موضوعية: |
*THERAPEUTIC use of lithium, *BIPOLAR disorder, *THERAPEUTICS, *DRUG development, *TRANSCRIPTION factors, *CATENINS, *ZEBRA danio |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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