Deficiency of diacylglycerol kinase induces lithium-sensitive mania-like behavior

The 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 DGK in the etiology of bipolar disorder (BPD). However, it is still unknown whether DGK is indeed related to BPD. In this study, we generated DGK-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 DGK deficits on psychomotor behavior. Intriguingly, DGK-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, DGK-KO mice showed impairment in glycogen synthase kinase (GSK) 3 signaling, which is closely related to BPD. These findings clearly support the linkage between BPD and DGK that is implicated by genome-wide association studies. Moreover, this study provides DGK-KO mice as a previously unrecognized model that reflects several features of human BPD with manic episodes and revealed an important role for DGK in regulating behavior and mood through, at least in part, GSK3 signaling.