Microglial 0-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 including transcription , translation, 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 such as microglia and astrocytes. In this study, we generated microgliaspecific O-GlcNAc 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 microglial morphology, lysosomal contents , and innate electrophysiological properties. Interestingly, the potassium channel Kv1 .3, which is known to be O-GlcNAcylated, exhibited an elevated expression leve l and channel conductance in the microglia located in the hippocampus of the OGT conditional KO mice. We also found that these Kv1 .3 abundant microglia specifically modulate hippocampal GABAergic synapses and inhibitory tone , causing a shift in E/1 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.