Li+ is a highly effective therapy for bipolar disorder, yet its use is limited by its narrow therapeutic window and frequent side effects. These limitations are accentuated in aging psychiatric patients and thus alternative therapies are needed. In addition, the pathogenesis of bipolar disorder in late life, as at any age, remains unknown and it is unclear how age-related changes in neuronal signal transduction pathways affect the pathogenesis of bipolar disease in the elderly. The mechanism of Li+ action is also unknown. Identification of its molecular targets should greatly accelerate the search for alternative therapies and should help to elucidate the pathophysiology of bipolar disease. We have proposed a novel target of Li+, the signaling molecule GSK-3, which mediates signaling by several types of peptide growth factors, including wnts, insulin, and epidermal growth factor. We have previously demonstrated that GSK-3 is inhibited by Li+ in vivo and in vitro. This application describes experiments to extend our observations to mammalian brain. The hypothesis to be tested is that alterations in GSK-3 activity in neurons will have specific effects on mouse behavior. Thus, wild-type and mutant GSK-3 (including dominant negative and putative constitutively activated forms) will be expressed in transgenic mice using a promoter that restricts expression to adult neurons of the central nervous system. Behavioral testing of transgenic mice will include photocell measurements of overall activity , Y maze, open field, and hole board activity monitoring. Hyperactive states induced with low dose amphetamine can be prevented by pretreatment with Li+ in mice. The experiments proposed here will test whether a dominant negative GSK-3 mutant will also block amphetamine induced hyperactivity and whether constitutively active GSK-3 will produce the hyperactive state. The response to Li+ in these transgenic animals will also be examined. Since GSK-3 mediated phosphorylation of tau protein has been implicated in the formation of paired helical filaments associated with Alzheimer's disease, the generation of transgenic mice overexpressing wild-type ans mutated GSK-3 may also be useful I the study of the pathogenesis of Alzheimer's disease.
