title: Deficiency of diacylglycerol kinase η induces lithium-sensitive mania-like behavior.
abstract: The η 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 DGKη in the etiology of bipolar disorder (BPD). However, it is still unknown whether DGKη is indeed related to BPD. In this study, we generated DGKη-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 DGKη deficits on psychomotor behavior. Intriguingly, DGKη-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, DGKη-KO mice showed impairment in glycogen synthase kinase (GSK) 3β signaling, which is closely related to BPD. These findings clearly support the linkage between BPD and DGKη that is implicated by genome-wide association studies. Moreover, this study provides DGKη-KO mice as a previously unrecognized model that reflects several features of human BPD with manic episodes and revealed an important role for DGKη in regulating behavior and mood through, at least in part, GSK3β signaling. Several genome-wide association studies have implicated diacylglycerol kinase (DGK) η gene in the etiology of bipolar disorder (BPD). In this study, we revealed that DGKη-knockout (KO) mice displayed an overall behavioral profile that is similar to mania of BPD and is lithium (BPD (mania) remedy)-sensitive. DGKη may regulate behavior and mood through, at least in part, glycogen synthase kinase (GSK) 3β signaling.
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Isozaki
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Komenoi
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Usuki
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Tomokata
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsutomo
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Animal Resource Development Unit and Genetic Engineering Team, Riken Center for Life Science Technologies, Kobe, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Bando
authors.affiliation: Animal Resource Development Unit and Genetic Engineering Team, Riken Center for Life Science Technologies, Kobe, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Sakane
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D001519:Behavior / Q000187:drug effects*; D001714:Bipolar Disorder / Q000378:metabolism*; D003863:Depression / Q000235:genetics / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000172:deficiency / Q000378:metabolism*; D055106:Genome-Wide Association Study / Q000379:methods; D006948:Hyperkinesis / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D008094:Lithium; D019852:Diacylglycerol Kinase
keywords: bipolar disorder; depression; diacylglycerol; diacylglycerol kinase; lithium; mania; phosphatidic acid; signal transduction