Hideki Okamoto, Bhavya Voleti, Mounira Banasr, Maysa Sarhan, Vanja Duric, Matthew J. Girgenti, Ralph J. DiLeone, Samuel S. Newton, Ronald S. DumanBackground: Despite recent interest in glycogen synthase kinase-3? (GSK-3?) as a target for the treatment of mood disorders, there has been very little work related to these illnesses on the upstream signaling molecules that regulate this kinase as well as downstream targets.Methods: With a focused microarray approach we examined the influence of different classes of antidepressants on Wnt signaling that controls GSK-3? activity as well as the transcription factors that contribute to the actions of GSK-3?.Results: The results demonstrate that Wnt2 is a common target of different classes of antidepressants and also show differential regulation of Wnt-GSK-3? signaling genes. Increased expression and function of Wnt2 was confirmed by secondary measures. Moreover, with a viral vector approach we demonstrate that increased expression of Wnt2 in the hippocampus is sufficient to produce antidepressant-like behavioral actions in well-established models of depression and treatment response.Conclusions: These findings demonstrate that Wnt2 expression and signaling is a common target of antidepressants and that increased Wnt2 is sufficient to produce antidepressant effects.