Microglial O-GlcNAcylati on Regulates Inhibitory Tone in the Hippocampus via the Kv1.3 Channel

Abstract

O- GlcNAcylati on is a post-translati onal modifi cati on criti cal for various cellular functi ons including transcripti on, translati on, signal transducti on, andprotein homeostasis. Notably, it has been shown that O-GlcNAcylati on modulates neuronal functi ons through "on-demand" protein modifi cati on.Despite this fact, it remains to be determined whether O-GlcNAcylati on is essenti al for glial cells such as microglia and astrocytes. In this study, wegenerated microglia-specifi c O-GlcNAc transferase (OGT) knockout (KO) mice to reveal the physiological roles of microglial O-GlcNAcylati on in thebrain. We found that the loss of O-GlcNAcylati on in microglia alters microglial morphology, lysosomal contents, and innate electrophysiologicalproperti es. Interesti ngly, the potassium channel Kv1.3, which is known to be O-GlcNAcylated, exhibited an elevated expression level and channelconductance in the microglia located in the hippocampus of the OGT conditi onal KO mice. We also found that these Kv1.3 abundant microgliaspecifi cally modulate hippocampal GABAergic synapses and inhibitory tone, causing a shift in E/I balance. Collecti vely, these data demonstrate thatmicroglia are important for tuning inhibitory tone in the hippocampus via O-GlcNAcylati on of the microglial proteins including the Kv1.3 channel.