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.
Neuropharmacology   113(Pt A): 490-501 (Journal)
Registered Authors
Kuznicki, Jacek
Behavior, Bipolar disorder, Lithium treatment, TCF7L2, Wnt signaling, β-catenin
MeSH Terms
  • Animals
  • Brain/cytology
  • Brain/drug effects
  • Brain/physiology
  • Cells, Cultured
  • Drug Administration Schedule
  • Lithium/administration & dosage*
  • Locomotion/drug effects
  • Locomotion/physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal*
  • Neurons/drug effects
  • Neurons/physiology*
  • Rats
  • Transcription Factor 7-Like 2 Protein/physiology*
  • Zebrafish
27793772 Full text @ Neuropharmacology
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes