Functional role of O-GlcNAcylation in serotonergic neurons

Abstract

Serotonergic neurons in the raphe nuclei project their axon fibers to almost all brain regions and are essential for diverse brain functions. Despite this functional significance, however, there still remains a good deal of uncertainty as to how serotonergic neurons and their activities are regulated at the molecular level. O-GlcNAcylation is a posttranslational modification that attaches O-linked β-N-acetylglucosamine (O-GlcNAc) to serine/threonine residue of proteins. O-GlcNAcylation plays a critical role in key cellular processes. Notably, O-GlcNAcylation and two related enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), are highly enriched in the brain and numerous neuronal proteins are known to be O-GlcNAcylated, while our understanding of the functional role of O-GlcNAcylation remains rudimentary in the brain. In this study, we investigated the functional role of O-GlcNAcylation in raphe serotonergic neurons. We found that genetic down-regulation of O-GlcNAcylation in serotonergic neurons causes a marked effect on cell survival. In addition, genetic up-regulation of O-GlcNAcylation led to the changes in synaptic functions of serotonergic neurons and serotonin-related behaviors. Given the recent findings about molecular and cellular heterogeneity of raphe serotonergic neurons, our findings will provide new insights into the molecular mechanisms by which serotonergic neurons and serotonin-related behaviors are controlled in the brain.