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.

Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

“…Several experiments tentatively implicated TCF7L2 deficiency in anxiety and depression. The silencing of Tcf7l2 in zebrafish by morpholinos antagonized the effect of lithium on dark‐induced locomotion , suggesting the involvement of TCF7L2 in the behavioral response to this medication for BD. Tcf7l2 haploinsufficiency increased anxiety‐like phenotypes in the light‐dark box test and contextual fear conditioning and reduced exploratory activity in some mouse strains .…”

“…Abundant expression of Tcf7l2 and Lef1 was specifically observed during postmitotic development and in adulthood in the thalamus, habenula, and some midbrain structures in vertebrates, including primates . These TCF7L2‐positive brain regions exhibited massive nuclear β‐catenin accumulation , and high reporter gene activity in Wnt reporter mice .…”

“…This accumulation appears to be independent of the upstream components of the Wnt signaling, but dependent of TCF7L2. In thalamic cells, the silencing of Tcf7l2 in thalamic neurons prevented β‐catenin from entering the nucleus , whereas inhibition of upstream canonical Wnt signaling had no effect on the localization of β‐catenin . The role of canonical Wnt/β‐catenin signaling in postmitotic neurons in the thalamo‐habenular domain is little understood compared with its role in cortical neural progenitors.…”

The role of CA1 CB1 receptors on lithium-induced spatial memory impairment in rats

“…Lithium is used for long-term treatment of bipolar disorder, and has a powerful effect for the prevention of manic/depressive recurrences (Geddes et al, 2010[ 22 ]). The clear mechanism of lithium remains unknown (Misztal et al, 2017[ 52 ]), but lithium can inhibit GSK3-β by increasing phosphorylation on the key serine residue (Ser9) (Jope, 2003[ 30 ]; Klein and Melton, 1996[ 35 ]). GSK3-β inhibition induced by lithium is an important contribution to its mood stabilizing therapeutic effects (Jope, 2011[ 29 ]).…”

Influence of CTNNB1 rs2953 polymorphism on schizophrenia susceptibility in Chinese Han population through modifying miR‐485 binding to CTNNB1

“…Valvezan et al reviewed and proposed that the canonical Wnt signaling pathway, which inhibits GSK‐3 to activate beta‐catenin‐dependent signaling, plays a critical role in diverse processes, including neurogenesis and central nervous system (CNS) development throughout adulthood. In classical therapy involving lithium for neuropsychiatric disorders, including SCZ and BD, lithium therapy for SCZ or BD stimulates the activation of the Wnt signaling pathway to promote neurogenesis . As a result, CTNNB1 , which probably participates in the occurrence and development of SCZ and BD, can be regarded as a candidate gene for these two major psychiatric disorders.…”