Systemic administration of the OGT inhibitor OSMI-1 normalizes hippocampal O-GlcNAcylation and improves recognition memory, redox balance, and brain mitochondrial homeostasis in a Rett syndrome mouse model.

Protein O-GlcNAcylation (O-GlcNAc) is a nutrient-responsive posttranslational modification (PTM). Proper regulation of brain O-GlcNAc levels is essential for the coupling between metabolic homeostasis and neuronal function. Abnormal O-GlcNAc levels in the brain are associated with neurodevelopmental and neurodegenerative diseases related to defects in energy metabolism. We investigated the levels and regulation of protein O-GlcNAc modification and related pathways through gene and protein expression analysis in the hippocampus of two well-established murine models of Rett syndrome (RTT), a monogenic neurodevelopmental disorder with metabolic components and a primary cause of severe intellectual disability in females. Increased protein O-GlcNAc levels, due to changes in the molecular machinery that controls O-GlcNAc production, transfer, and removal, were observed in the hippocampus of the two RTT mouse models (MeCP2-BIRD and MeCP2-308 models). Remarkably, systemic administration of the OGT inhibitor OSMI-1 restored O-GlcNAc brain homeostasis and rescued brain mitochondrial defects and redox alterations in the RTT mouse hippocampus. The OSMI-1 treatment also induced a normalization of the cognitive performance of RTT mice in novel object recognition tests and reduced peripheral oxidative stress. These findings provide new evidence of an imbalance in nutrient-sensing O-GlcNAc in the RTT mouse hippocampus, suggesting that restoring brain O-GlcNAc homeostasis might represent a promising therapeutic approach for RTT.