The g isozyme of diacylglycerol kinase (DGK) is highly expressed in the hippocampus and Purkinje cells in the central nervous system. Recently, several genome-wide association studies have implicated DGKg in the etiology of bipolar disorder (BPD). However, it is still unknown whether DGKg is indeed related to BPD. In this study, we generated DGKg-knockout (KO) mice and performed behavioral tests such as the open field test, the elevated plus maze test and tail suspension test using the KO mice to investigate the effects of DGKg deficits on psychomotor behavior. Intriguingly, DGKg-KO mice displayed an overall behavioral profile that is similar to human mania, including hyperactivity, less anxiety and less depression-like behavior. In addition, these phenotypes were significantly attenuated by the administration of a BPD (mania) remedy, namely, lithium. Moreover, DGKg-KO mice showed impairment in glycogen synthase kinase (GSK) 3b signaling, which is closely related to BPD. These findings clearly support the linkage between BPD and DGKg that is implicated by genome-wide association studies. Moreover, this study provides DGKg-KO mice as a previously unrecognized model that reflects several features of human BPD with manic episodes and revealed an important role for DGKg in regulating behavior and mood through, at least in part, GSK3b signaling.

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