UC San Diego

The role of post-translational modifications in the brain such as phosphorylation

and ubiquitination have been well studied. However, the role of O-GlcNAcylation in

distinct subpopulations of neurons remains unknown. This post-translational

modification is an addition of single sugar moiety O-GlcNAc, derived from glucose

metabolism, to serine or threonine residue of proteins. O-GlcNAcylation is catalyzed by

O-GlcNAc transferase (OGT), a highly expressed metabolic sensor enzyme in the brain,

shown to be a gatekeeper for neuronal function and health. Here, we investigated the role

of OGT and O-GlcNAc dynamics in the brain. First, we demonstrated under the fasted

state, brain regions such as the paraventricular nucleus of hypothalamus, cortex and

cerebellum, have significant reduction in O-GlcNAc levels. While the hippocampus

regions, CA3 and dentate gyrus, have increased levels of O-GlcNAcylation. Then in order

to investigate the role of O-GlcNAcylation in Parvalbumin-positive inhibitory

interneurons (PV), we generated a PV-specific-OGT knockout mouse line (PV.OGTKO).

Our detailed behavioral and histological analysis indicated that loss of OGT in PV

neurons leads to lower survival rates, motor defects, and loss of PV neurons. Overall, our

results suggest the OGT plays crucial role in PV neuronal health and survival.