Increased O-GlcNAcylation rapidly decreases GABAAR currents in hippocampus yet depresses neuronal output

Abstract

O-GlcNAcylation, a post-translational modification involving O-linkage of {beta}-N-acetylglucosamine to Ser/Thr residues on target proteins, is increasingly recognized as a critical regulator of brain function in health and disease. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. An acute increase in O-GlcNAcylation induces long-term depression (LTD) of excitatory transmission at hippocampal CA3-CA1 synapses, and depresses hyperexcitable circuits in vitro and in vivo. Yet, no study has investigated how O-GlcNAcylation modulates the efficacy of inhibitory neurotransmission. Here we show an acute increase in O-GlcNAc dampens GABAergic currents onto principal cells in rodent hippocampus likely through a postsynaptic mechanism, and has a variable effect on the excitation/inhibition balance. The overall effect of increased O-GlcNAc is reduced synaptically-driven spike probability via synaptic depression and decreased intrinsic excitability. Our results position O-GlcNAcylation as a novel regulator of the overall excitation/inhibition balance and neuronal output.