Background: Mounting evidence suggests that bipolar disorder symptoms could be favorably influenced by modification of glycogen synthase kinase-3 (GSK-3) activity. Specifically, the well known antimanic and mood stabilizing medications lithium, valproate, olanzapine and clozapine have been shown to inhibit GSK-3 activity. GSK-3 is phosphorylated and thus inhibited by protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms. The present study explored, whether PKB/SGK-dependent GSK-3 regulation influences the behavior of mice. Methods: Gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK-3Α, Β (gsk-3^KI) were compared to corresponding wild type mice (gsk-3^WT). The mice were analyzed by open-field, light-dark (LD-) box, O-maze, emergence test, object exploration test and forced swimming test (FST). Results: In open-field, LD-box and O-maze, gsk-3^KI mice displayed a hyperactive and more curious phenotype when compared to wild type mice. Speed and total distance moved as well as rearings were significantly increased in gsk-3^KI compared to gsk-3^WT mice. In the O-maze, gsk-3^KI mice tended to travel a larger distance in the open, unprotected area thangsk-3^WT mice, and performed significantly more unprotected head dips suggesting decreased anxiety behavior. In the forced swimming test, the immobility time was significantly decreased in gsk-3^KI mice indicating a phenotype less prone to depression. Moreover, gsk-3^KI mice were less sensitive to the application of chronic mild stress and showed a decreased HPA axis activity. Conclusions: The present observations disclose a significant role of PKB/SGK-dependent regulation of GSK-3 in the control of activity, anxiety and proneness to depression. Accordingly, mice expressing SGK/PKB resistant GSK-3 may be a valuable model of hyperactivity and mania.