Abstract
Lithium inhibits glycogen synthase kinase-3 (GSK-3) at therapeutic concentrations; however, it is unclear if this inhibition and its downstream effects on specific signaling pathways are relevant to the treatment of bipolar disorder and depression. One of the targets of GSK-3 is the transcription factor β-catenin. Normally active GSK-3 phosphorylates β-catenin, leading to its degradation. Inhibition of GSK-3 therefore increases β-catenin. We have utilized transgenic mice to investigate the behavioral consequences of CNS β-catenin overexpression. Transgenic mice overexpressing β-catenin demonstrated behavioral changes similar to those observed following the administration of lithium, including decreased immobility time in the forced swim test (FST). Further, we show that although acute administration of lithium and overexpression of the β-catenin transgene inhibits d-amphetamine-induced hyperlocomotion, neither lithium nor the β-catenin transgene prevents d-amphetamine-induced sensitization, as measured by locomotor activity. Both lithium-treated and β-catenin mice had an elevated response to d-amphetamine following multiple administrations of the stimulant, though the difference in absolute locomotion was maintained throughout the sensitization time-course. Neither acute lithium nor β-catenin overexpression had an effect on d-amphetamine-induced stereotyped behavior. The results of this study, in which β-catenin transgenic mice exhibited behaviors identical to those observed in lithium-treated mice, are consistent with the hypothesis that the behavioral effects of lithium in these models are mediated through its direct inhibition of GSK-3 and the consequent increase in β-catenin. By associating the behavioral effects of lithium with β-catenin levels, these data suggest that increasing β-catenin might be a novel therapeutic strategy for mood disorders.
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Acknowledgements
We thank Dr Charles Eberhart (Johns Hopkins University) for the β-catenin transgenic mice, Dr Francois Vautier for assistance with the Morris water maze protocol, and David A Luckenbaugh, NIMH Mood and Anxiety Disorders Program Biostatistician, for statistical assistance. This research was supported by the Intramural Research Program of the National Institute of Mental Heath, the Foundation for the National Institutes of Health (Neuroscience Research Fellowship (TDG)), the National Association for Research on Schizophrenia and Depression (Young Investigator Award to TDG and HE), and the Stanley Research Foundation (HKM). The authors have no conflicts of interest, financial or otherwise.
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Gould, T., Einat, H., O'Donnell, K. et al. β-Catenin Overexpression in the Mouse Brain Phenocopies Lithium-Sensitive Behaviors. Neuropsychopharmacol 32, 2173–2183 (2007). https://doi.org/10.1038/sj.npp.1301338
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DOI: https://doi.org/10.1038/sj.npp.1301338
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