Hwang, Hongik Rhim, Hyewhon 2024-01-19T20:03:53Z 2024-01-19T20:03:53Z 2021-09-02 2019-05 2045-2322 https://pubs.kist.re.kr/handle/201004/120057 Post-translational modification (PTM) plays a critical role in increasing proteome complexity and diversifying protein functions. O-GlcNAc modification is a reversible, dynamic and highly abundant PTM catalyzed by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), regardless of substrates. The two enzymes are particularly enriched in the brain, and recent proteomic studies identified that a large number of neuron-specific proteins undergo O-GlcNAc modification. In addition, pathological conditions with aberrant O-GlcNAcylation such as diabetes and obesity are associated with the higher risk of cognitive decline and memory impairment. However, despite its prevalence in the brain, functional significance of O-GlcNAcylation in regulating neuronal properties remains unclear at the molecular level. Here, we report that an acute increase in O-GlcNAcylation induced by pharmacological inhibition of OGA significantly reduces the intrinsic excitability of hippocampal CA1 neurons through the cooperative modulation of multiple voltage-gated ion channels. Moreover, elevated O-GlcNAcylation also suppresses excitatory synaptic transmission at Schaffer collateral-CA1 synapses through the removal of GluA2-containing AMPA receptors from postsynaptic densities. Collectively, our findings demonstrate that a change in O-GlcNAcylation levels dynamically regulates hippocampal activity at both intrinsic and synaptic levels, providing a mechanistic link between dysregulated O-GlcNAcylation and hippocampal dysfunction. English Nature Publishing Group Acutely elevated O-GlcNAcylation suppresses hippocampal activity by modulating both intrinsic and synaptic excitability factors Article 10.1038/s41598-019-43017-9 1 Scientific Reports, v.9 Scientific Reports 9 Y scie scopus 000467709100029 2-s2.0-85065697360 Multidisciplinary Sciences Science & Technology - Other Topics Article GLCNAC TRANSFERASE AMPA RECEPTORS NEURONAL EXCITABILITY NUTRIENT REGULATION GENE-EXPRESSION PHOSPHORYLATION IDENTIFICATION PLASTICITY GLYCOSYLATION CHANNELS