A MOLECULAR MECHANISM FOR THE EFFECT OF LITHIUM ON DEVELOPMENT

Lithium, one of the most effective drugs for the treatment of bipolar (manic-depressive) disorder, also has dramatic effects on morphogenesi s in the early development of numerous organisms. How lithium exerts t hese diverse effects is unclear, but the favored hypothesis is that li thium acts through inhibition of inositol monophosphatase (IMPase). We show here that complete inhibition of IMPase has no effect on the mor phogenesis of Xenopus embryos and present a different hypothesis to ex plain the broad action of lithium. Our results suggest that lithium ac ts through inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), which regulates cell fate determination in diverse organisms includin g Dictyostelium, Drosophila, and Xenopus. Lithium potently inhibits GS K-3 beta activity (K-i = 2 mM), but is not a general inhibitor of othe r protein kinases. In support of this hypothesis, lithium treatment ph enocopies loss of GSK-3 beta function in Xenopus and Dictyostelium. Th ese observations help explain the effect of lithium on cell-fate deter mination and could provide insights into the pathogenesis and treatmen t of bipolar disorder.