O‐GlcNAcylation of the AMPA receptor GluA2 Subunit May Contribute to LTD at Hippocampal CA3‐CA1 Synapses

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. Because synaptic function is tightly regulated by serine phosphorylation of synaptic proteins, it is likely that serine O‐GlcNAcylation also regulates synaptic efficacy. 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 (O‐GlcNAc‐LTD) (85% ± 2.6% and 81% ± 4.1% of baseline, respectively) and causes decrementing long‐term potentiation (control: 135% ± 6.2%, Thiamet‐G: 93% ± 7.1% of baseline). Because PKC‐dependent phosphorylation of Ser‐880 on the AMPAR GluA2 subunit triggers AMPAR endocytosis, we investigated whether GluA2 is O‐GlcNAcylated during O‐GlcNAc LTD, and if this occurs at Ser‐880. Indeed, GluA2, but not GluA1, subunits are O‐GlcNAcylated, without modifying phospho‐Ser‐880 levels. These results suggest that GluA2 O‐GlcNAcylation may contribute to expression of O‐GlcNAc LTD, with a mechanism independent of phospho‐Ser880.