Microglial O-GlcNAcylation regulates inhibitory tone in the hippocampus via the Kv1.3 channel

Abstract

O- GlcNAcylation is a post-translational modification critical for various cellular functions such as regulation of gene expression, signal transduction, and protein homeostasis. Notably, it has been shown that O-GlcNAcylation modulates neuronal functions through "on-demand" protein modification. Despite this fact, it remains to be determined whether O-GlcNAcylation is essential for glial cells. In this study, we generated microglia-specific OGlcNAc transferase (OGT) knockout (KO) mice to reveal the physiological roles of microglial O-GlcNAcylation in the brain. We found that the loss of O-GlcNAcylation in microglia alters the innate biology. Interestingly, the potassium channel Kv1.3, which is known to be O-GlcNAcylated, exhibited an elevated expression level and channel conductance in hippocampal OGT cKO microglia. We also found that these Kv1.3 abundant microglia specifically modulate hippocampal GABAergic synapses and inhibitory tone, causing a shift in E/I balance. Collectively, these data demonstrate that microglia are important for tuning inhibitory tone in the hippocampus via O-GlcNAcylation of the microglial proteins including the Kv1.3 channel.