Abstract
Bipolar disorder (BP) is a debilitating psychiatric disorder, affecting ∼2% of the worldwide population, for which the etiological basis, pathogenesis, and neurocircuitry remain poorly understood. Individuals with BP suffer from recurrent episodes of mania and depression, which are commonly treated with the mood stabilizer lithium. However, nearly half of BP patients do not respond adequately to lithium therapy and the clinically relevant mechanisms of lithium for mood stabilization remain elusive. Here, we modeled lithium responsiveness using cellular assays of glycogen synthase kinase 3 (GSK-3) signaling and mood-related behavioral assays in inbred strains of mice that differ in their response to lithium. We found that activating AKT through phosphosrylation of a key regulatory site (Thr308) was associated with lithium response—activation of signaling pathways downstream of GSK-3 in cells and attenuation of mood-related behaviors in mice—and this response was attenuated by selective and direct inhibition of AKT kinase activity. Conversely, the expression of constitutively active AKT1 in both the cellular and behavioral assays conferred lithium sensitivity. In contrast, selective and direct GSK-3 inhibition by the ATP-competitive inhibitor CHIR99021 bypassed the requirement for AKT activation and modulated behavior in both lithium-responsive and non-responsive mouse strains. These results distinguish the mechanism of action of lithium from direct GSK-3 inhibition both in vivo and in vitro, and highlight the therapeutic potential for selective GSK-3 inhibitors in BP treatment.
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Acknowledgements
We thank Drs Li-Huei Tsai, Daniel Fass, Jon Madison, Pamela Sklar, Melanie Leussis, and Roy Perlis for critical reading of the paper. We thank Dr Jennifer Moran for technical assistance with HT-22 cell genotype analysis. We thank Dr. Michael Moyer for assistance with the AKT inhibitor experiments. We thank Drs M Mazei-Robison and E Nestler for providing HSV-AKT1 constructs. This work was supported by grants from the National Institutes of Health (RL1GM084437 to EMS, administratively linked to RL1CA133834, RL1HG004671, and UL1RR024924; MH087442-01 to JP and SJH) and the Stanley Medical Research Institute (to EMS, SJH, TLP). RTM is an investigator of the HHMI.
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Pan, J., Lewis, M., Ketterman, J. et al. AKT Kinase Activity Is Required for Lithium to Modulate Mood-Related Behaviors in Mice. Neuropsychopharmacol 36, 1397–1411 (2011). https://doi.org/10.1038/npp.2011.24
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DOI: https://doi.org/10.1038/npp.2011.24
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