RT Journal Article SR Electronic T1 DGKγ knockout mice show impairments in cerebellar motor coordination, LTD and the dendritic development of Purkinje cells through the activation of PKCγ JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0319-19.2020 DO 10.1523/ENEURO.0319-19.2020 A1 Ryosuke Tsumagari A1 Sho Kakizawa A1 Sakiko Kikunaga A1 Yoshitaka Fujihara A1 Shuji Ueda A1 Minoru Yamanoue A1 Naoaki Saito A1 Masahito Ikawa A1 Yasuhito Shirai YR 2020 UL http://www.eneuro.org/content/early/2020/02/05/ENEURO.0319-19.2020.abstract AB Diacylglycerol kinase γ (DGKγ) regulates protein kinase C (PKC) activity by converting diacylglycerol (DG) to phosphatidic acid (PA). DGKγ directly interacts with PKCγ and is phosphorylated by PKCγ, resulting in the upregulation of lipid kinase activity. PKC dysfunction impairs motor coordination, indicating that the regulation of PKC activity is important for motor coordination. DGKγ and PKC are abundantly expressed in cerebellar Purkinje cells. However, the physiological role of DGKγ has not been elucidated. Therefore, we developed DGKγ knockout (KO) mice and tested their cerebellar motor coordination. In DGKγ KO mice, cerebellar motor coordination and long-term depression (LTD) were impaired, and the dendrites of Purkinje cells from DGKγ KO mice were significantly retracted. Interestingly, treatment with the cPKC inhibitor Gö6976 rescued the dendritic retraction of primary cultured Purkinje cells from DGKγ KO mice. In contrast, treatment with the PKC activator 12-o-tetradecanoylphorbol 13-acetate (TPA) reduced morphological alterations in the dendrites of Purkinje cells from WT mice. In addition, we confirmed the upregulation of PKCγ activity in the cerebellum of DGKγ KO mice and rescued impaired LTD in DGKγ KO mice with a PKCγ specific inhibitor. Furthermore, impairment of motor coordination observed in DGKγ KO mice was rescued in tm1c mice with DGKγ reexpression induced by the FLP-FRT recombination system. These results indicate that DGKγ is involved in cerebellar LTD and the dendritic development of Purkinje cells through the regulation of PKCγ activity, and thus contributes to cerebellar motor coordination.Significance Statement The only output neurons of the cerebellum, Purkinje cells, regulate long-term depression (LTD). LTD and the dendritic development of Purkinje cells are important for motor function. Many studies have revealed functional correlations between signaling molecules involved in the mechanisms of motor coordination; however, we still do not have enough knowledge to understand the overall concept. Here, we show that the functional correlation between diacylglycerol kinase γ (DGKγ) and protein kinase C γ (PKCγ) contributes to motor coordination. DGKγ regulates the activity of PKCγ, which is an important factor in LTD and the dendritic development of Purkinje cells, allowing PKC to function precisely as a mediator of motor coordination.