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Depression caused by genetic and environmental factors is acomplicated disease. Here, it is demonstrated that glycogen synthase kinase-3$\beta$ is highly expressed and phosphorylated in the brain of a chronic stress mouse. Inhibition of glycogen synthase kinase-3$\beta$ leads to decreased depression-like symptoms which manifest in open-field test, tail-suspension test, forced-swim test, and a novelty suppressed feeding test. It was also found that $\beta$-catenin is attenuated, and its target genes Cyclin D1 and c-Myc are down-regulated. Glycogen synthase kinase-3$\beta$ was also found to inhibit Erk-Creb-BDNF signaling. These results show that glycogen synthase kinase-3$\beta$ may promote the progression of depression. Therefore, targeting glycogen synthase kinase-3$\beta$ may be an effective therapeutic strategy.