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.
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