Abstract

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.

Highlights

  • Post-translational modification (PTM) is a covalent modification of proteins that occurs following or during translation, contributing to diversifying protein functions

  • The addition of O-GlcNAc is mediated by O-GlcNAc transferase (OGT), and UDP-GlcNAc serves as an immediate donor (Fig. 1a)

  • Based on our observation that O-GlcNAcylation levels modulate the intrinsic properties of neurons as well as excitatory synaptic transmission, we examined whether altered O-GlcNAcylation affects basal calcium levels and ligand-induced calcium influx in hippocampal neurons

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Summary

Introduction

Post-translational modification (PTM) is a covalent modification of proteins that occurs following or during translation, contributing to diversifying protein functions. Www.nature.com/scientificreports in neuronal development and synaptic plasticity[19,20,21,22,23,24], such as CREB, CaMKII, and GluA2, and the expression of OGT and OGA enzymes is highly enriched in multiple brain regions[25], including the hippocampus, cortex and hypothalamus. OGT is involved in the maturity of excitatory synapses[35], and increasing O-GlcNAcylation levels were shown to depress epileptiform activity in the hippocampus[36] These findings together implicate the role of O-GlcNAcylation in modulating neuronal excitability and excitatory synaptic transmission, but the underlying molecular mechanism remains elusive. Our results provide mechanistic insight into the modulation of hippocampal excitability via O-GlcNAcylation, and suggest a potential contribution of suppressed hippocampal activity to the cognitive deficits associated with dysregulated O-GlcNAcylation levels in the brain

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