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.

Diacylglycerol kinase (DGK) participates in regulating the intracellular concentrations of two bioactive lipids, diacylglycerol and phosphatidic acid. DGKη1 is a type II isozyme that contains a pleckstrin homology (PH) domain and a pair of C1 domains at the N-terminus and separated catalytic domains (catalytic subdomain-a and b). We previously reported that DGKη1 expressed in COS-7 cells is translocated from the cytoplasm to punctate granules that partially include endosomes in response to stress stimuli such as osmotic shock. However, the biochemical properties of the stress-dependent behaviour of DGKη1 remain unknown. Here, we have found that DGKη1 is redistributed from the cytosol to the non-ionic detergent (Nonidet P-40)-resistant membrane (DRM) in response to osmotic shock. Our results strongly suggested that the Nonidet P-40 insolubility of DGKη1 is due to neither cytoskeleton localization nor lipid raft association, implying that DGKη1 is distributed to detergent-resistant membrane microdomains that have a low lipid-to-protein ratio. We revealed, using a series of DGKη1 deletion mutants, that the PH and C1 domains play a pivotal role in osmotic shock-dependent DRM redistribution, whereas catalytic subdomain-a negatively regulates the event.

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