DGKγ Knock-Out Mice Show Impairments in Cerebellar Motor Coordination, LTD, and the Dendritic Development of Purkinje Cells through the Activation of PKCγ

Tsumagari, R., Kakizawa, S., Kikunaga, S., Fujihara, Y., Ueda, S., Yamanoue, M., . . . Shirai, Y. (2020). Dgkg knock-out mice show impairments in cerebellar motor coordination, ltd, and the dendritic development of purkinje cells through the activation of pkcg. ENeuro, 7(2) doi:10.1523/ENEURO.0319-19.2020
Diacylglycerol kinase g (DGKg) regulates protein kinase C (PKC) activity by converting DG to phosphatidic acid (PA). DGKg directly interacts with PKCg and is phosphorylated by PKCg, 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. DGKg and PKC are abundantly expressed in cerebellar Purkinje cells. However, the physiological role of DGKg has not been elucidated. Therefore, we developed DGKg knock-out (KO) mice and tested their cerebellar motor coordination. In DGKg KO mice, cerebellar motor coordination and long-term depression (LTD) were impaired, and the dendrites of Purkinje cells from DGKg KO mice were significantly retracted. Interestingly, treatment with the cPKC inhibitor Gö6976 (Gö) rescued the dendritic re-traction of primary cultured Purkinje cells from DGKg KO mice. In contrast, treatment with the PKC activator 12-o-tetradecanoylphorbol 13-acetate (TPA) reduced morphologic alterations in the dendrites of Purkinje cells from wild-type (WT) mice. In addition, we confirmed the upregulation of PKCg activity in the cerebellum of DGKg KO mice and rescued impaired LTD in DGKg KO mice with a PKCg-specific inhibitor. Furthermore, im-pairment of motor coordination observed in DGKg KO mice was rescued in tm1c mice with DGKg reexpres-sion induced by the FLP-flippase recognition target (FRT) recombination system. These results indicate that DGKg is involved in cerebellar LTD and the dendritic development of Purkinje cells through the regulation of PKCg activity, and thus contributes to cerebellar motor coordination.