|ZFIN ID: ZDB-PUB-161030-3|
TCF7L2 mediates the cellular and behavioral response to chronic lithium treatment in animal models
Misztal, K., Brozko, N., Nagalski, A., Szewczyk, L.M., Królak, M., Brzozowska, K., Kuznicki, J., Wisniewska, M.B.
|Source:||Neuropharmacology 113(Pt A): 490-501 (Journal)|
|Registered Authors:||Kuznicki, Jacek|
|Keywords:||Behavior, Bipolar disorder, Lithium treatment, TCF7L2, Wnt signaling, β-catenin|
|PubMed:||27793772 Full text @ Neuropharmacology|
Misztal, K., Brozko, N., Nagalski, A., Szewczyk, L.M., Królak, M., Brzozowska, K., Kuznicki, J., Wisniewska, M.B. (2017) TCF7L2 mediates the cellular and behavioral response to chronic lithium treatment in animal models. Neuropharmacology. 113(Pt A):490-501.
ABSTRACTThe 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.