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.