title: TCF7L2 mediates the cellular and behavioral response to chronic lithium treatment in animal models.
abstract: 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.
authors: International Institute of Molecular and Cell Biology, Laboratory of Neurodegeneration, Warsaw, Poland.
authors: Katarzyna
authors: K
authors: Misztal
authors: 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.
authors: Nikola
authors: N
authors: Brozko
authors: International Institute of Molecular and Cell Biology, Laboratory of Neurodegeneration, Warsaw, Poland; University of Warsaw, Centre of New Technologies, Laboratory of Molecular Neurobiology, Poland.
authors: Andrzej
authors: A
authors: Nagalski
authors: International Institute of Molecular and Cell Biology, Laboratory of Neurodegeneration, Warsaw, Poland; Postgraduate School of Molecular Medicine, Warsaw, Poland.
authors: Lukasz M
authors: LM
authors: Szewczyk
authors: University of Warsaw, College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, Poland.
authors: Marta
authors: M
authors: Krolak
authors: 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.
authors: Katarzyna
authors: K
authors: Brzozowska
authors: International Institute of Molecular and Cell Biology, Laboratory of Neurodegeneration, Warsaw, Poland.
authors: Jacek
authors: J
authors: Kuznicki
authors: International Institute of Molecular and Cell Biology, Laboratory of Neurodegeneration, Warsaw, Poland; University of Warsaw, Centre of New Technologies, Laboratory of Molecular Neurobiology, Poland. Electronic address: m.wisniewska@uw.edu.pl.
authors: Marta B
authors: MB
authors: Wisniewska
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D008094:Lithium / Q000008:administration & dosage*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D058118:Transcription Factor 7-Like 2 Protein / Q000502:physiology*; D015027:Zebrafish
chemical_list: C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D008094:Lithium
keywords: Behavior; Bipolar disorder; Lithium treatment; TCF7L2; Wnt signaling; β-catenin