Ogt Deficiency Induces Abnormal Cerebellar Function and Behavioral Deficits of Adult Mice through Modulating RhoA/ROCK Signaling

Previous studies have shown the essential roles of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in neuronal development, function and neurologic diseases. However, the function of Ogt and O-GlcNAcylation in the adult cerebellum has not been well elucidated. Here, we have found that cerebellum has the highest level of O-GlcNAcylation relative to cortex and hippo -campus of adult male mice. Specific deletion of Ogt in granule neuron precursors (GNPs) induces abnormal morphology and decreased size of the cerebellum in adult male Ogt deficient [conditional knock-out (cKO)] mice. Adult male cKO mice show the reduced density and aberrant distribution of cerebellar granule cells (CGCs), the disrupted arrangement of Bergman glia (BG) and Purkinje cells. In addition, adult male cKO mice exhibit aberrant synaptic connection, impaired motor coordina-tion, and learning and memory abilities. Mechanistically, we have identified G-protein subunit a12 (Ga12) is modified by Ogt-mediated O-GlcNAcylation. O-GlcNAcylation of Ga12 facilitates its binding to Rho guanine nucleotide exchange factor 12 (Arhgef12) and consequently activates RhoA/ROCK signaling. RhoA/ROCK pathway activator LPA can rescue the developmen-tal deficits of Ogt deficient CGCs. Therefore, our study has revealed the critical function and related mechanisms of Ogt and O-GlcNAcylation in the cerebellum of adult male mice.

Automated summary

Previous studies have demonstrated the important roles of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in neuronal development, function, and neurologic diseases. However, the functions of Ogt and O-GlcNAcylation in the adult cerebellum have not been well understood. This study revealed that the cerebellum of adult male mice has the highest level of O-GlcNAcylation compared to the cortex and hippocampus. Deletion of Ogt specifically in granule neuron precursors (GNPs) resulted in abnormal cerebellar morphology, impaired motor coordination, and learning and memory abilities in adult male mice.