O‐GlcNAcylation Modulates Hippocampal Plasticity and Alters Hippocampal Dependent Learning and Memory

Abstract

O‐GlcNAcylation is a dynamic posttranslational modification involving O‐linked addition of β‐N‐acetylglucosamine (GlcNAc) to serine/threonine residues on nucleocytoplasmic proteins. Hippocampal neurons express high levels of OGT and OGA, enzymes that add and remove O‐GlcNAc moieties. We investigated whether increasing O‐GlcNAcylation, with glucosamine or the OGA inhibitor Thiamet‐G, modulates synaptic transmission at CA3‐CA1 synapses in hippocampus, a brain region required for learning and memory. We find that increased O‐GlcNAcylation induces a novel long‐term depression (glucosamine: 85% ± 2.6% and Thiamet‐G: 81% ± 4.1% of baseline) and causes decrementing long‐term potentiation (control: 137 ± 4%, Thiamet‐G: 122 ± 6% of baseline). We also find that AMPA receptor GluA2, but not GluA1, subunits are O‐GlcNAcylated. We further demonstrate that increasing O‐GlcNAcylation in vivo interferes with novel object recognition while contextual fear conditioning is intact. These findings support the notion that an acute change in O‐GlcNAcylation of synaptic proteins is a novel fundamental mechanism capable of modulating synaptic efficacy and memory processing.