GSK-3 Signaling: Targeting Actions of Mood Stablizing

National Institute Of Mental Health

Investigators

Abstract

Glycogen synthase kinase-3 (GSK-3), is directly inhibited by lithium, and as such is an interesting candidate as a potential target for novel therapeutics. There is tremendous interest in GSK-3 inhibitors as novel therapeutic agents, and selective, small molecule compounds are rapidly being developed for a broad range of maladies including diabetes, Alzheimer's disease, stroke, and inflammation. With convincing preclinical evidence, it is likely that those medications developed will be utilized in bipolar disorder trials. Although GSK-3 was identified as in vitro target of lithium in 1996, the degree of inhibition of this enzyme in the adult mammalian brain at therapeutically relevant concentrations has not been established and was an impediment to future bipolar disorder trials directed at GSK-3 inhibition. In a manuscript currently in press in Neuropsychopharmacology, we showed, using subcellular fractionation and real-time PCR, that treatment with lithium and valproic acid at therapeutic serum concentrations postranslationally regulates ?O-catenin (a GSK-3 target and important transcription factor) in the rat brain, suggesting that lithium significantly inhibits brain GSK-3 in vivo at concentrations relevant for the treatment of bipolar disorder. The finding that two structurally dissimilar mood-stabilizing medications exert similar effects on ?O-catenin, suggests a possible importance of this protein in the treatment of bipolar disorder. To further address importance of this transcription factor, I am collaborating with Charles Eberhart (Johns Hopkins University) to investigate the behavioral and biochemical manifestations of over-expression of ?O-catenin in the adult brain of transgenic mice. Additional studies currently underway plan to access the effects of novel, specific, GSK-3 inhibitors in rodent behavioral models. It is exciting that this work may help facilitate clinical trials. However, a major concern in the development of GSK-3 inhibitors has been that the Wnt signaling pathway!Vof which GSK-3 is an important intermediary molecule!Vis implicated in many human cancers. We therefore investigated, and recently published in Pharmacological Research, a manuscript describing the effects of lithium in a murine model predisposed to the formation of tumors of the Wnt pathway!Xthe adenomatous polyposis coli (APC) mouse; we found that 60 days of lithium treatment did not increase the number of tumors. Similar studies to our own APC mouse experiments will be critical for establishing the safety of novel GSK-3 inhibitors prior to use in humans. In addition to the studies designed to understand the role of GSK-3 in bipolar disorder pathophysiology and treatment, we are also assessing the effects of mood stabilizer treatments in a line of mice containing a CRE-?O galactosidase reporter construct (through a collaboration with Daniel Storm, University of Washington). Both lithium and valproic acid have been shown by our group to increase the levels of the activated form of CREB; the results of these studies with CRE-?O galactosidase reporter mice may provide more evidence for this observation, in addition to providing a greater degree of regional and temporal specificity.