Lithium has been used in the treatment of bipolar disorder for 50 years, and yet its mechanism of action remains unclear. We wish to apply basic research methods to the study of mental health in order to identify and characterize the molecular targets of lithium salts. This approach may allow the development of new and safer therapeutic agents and should also help to elucidate the neuronal signaling pathways involved in the pathogenesis of this common and debilitating disorder. The goal of this proposal is to test a new hypothesis for the molecular mechanism of lithium action using model organisms that are dramatically affected by exposure to lithium. Our hypothesis is that the signaling molecule glycogen synthase kinase-3 (GSK-3) is an important target of lithium action in diverse systems. This hypothesis offers a common mechanism to explain the diverse effects of lithium on embryogenesis, insulin signaling pathways, hematopoiesis, and other processes and could also be extended to explain the neuropsychiatric effects of lithium. The hypothesis is supported by our data that GSK-3 is inhibited by lithium in vitro and in vivo in Xenopus laevis embryos. Lithium also appears to inhibit GSK-3 in yeast, leading to phenotypes that parallel mutations in GSK-3. This observation provides a powerful genetic screen to identify mutations in GSK-3 that can be employed to examine whether GSK-3 is the sole or primary target of lithium in vivo. The Xenopus embryo, which shows a dramatic teratogenic response to lithium treatment, offers an ideal model system to test our hypothesis using mutated GSK-3 expressed ectopically in embryos. In addition, we have developed several in vivo assays for GSK-3 activity which can now be applied to mammalian brain to test whether lithium also inhibits neuronal GSK-3beta in vivo. The experiments described here will form the basis for future experiments with transgenic mice expressing GSK-3 mutants to determine whether inhibition of GSK-3 is both necessary and sufficient for its neuropsychiatric effects in mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH058324-02
Application #
2873097
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Program Officer
Brady, Linda S
Project Start
1998-04-01
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Mazumdar, Jolly; O'Brien, W Timothy; Johnson, Randall S et al. (2010) O2 regulates stem cells through Wnt/?-catenin signalling. Nat Cell Biol 12:1007-13
Huang, Jian; Zhang, Yi; Bersenev, Alexey et al. (2009) Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J Clin Invest 119:3519-29
O'Brien, W Timothy; Klein, Peter S (2009) Validating GSK3 as an in vivo target of lithium action. Biochem Soc Trans 37:1133-8
O'Brien, W Timothy; Klein, Peter S (2007) Regulation of glycogen synthase kinase-3 in patients with affective disorders. Biol Psychiatry 61:139-41
Shaldubina, Alona; Johanson, Roy A; O'Brien, W Timothy et al. (2006) SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior. Mol Genet Metab 88:384-8
Yanfeng, Wang A; Tan, Change; Fagan, Robert J et al. (2006) Phosphorylation of frizzled-3. J Biol Chem 281:11603-9

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