Hippocampal O-GlcNAc homeostasis sustains memory reconsolidation amidst stress hormone exposure

Memory is not always reliable, inherently malleable. The malleability enables organisms to adapt their behavior based on future predictions, increasing survival odds. O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as a modulator of memory, notwithstanding, its impact on memory malleability remains to be comprehensively elucidated. Here, we report that the reliable prediction-mediated strengthening or incomplete reminder-mediated updating of original memories, a process called reconsolidation can alter memory malleability, which is impaired in mice (C57BL/6J, males) under stress. Pharmacologically enhancing O-GlcNAc levels afford dynamic and phase-specific protection of reconsolidation. Meanwhile, overexpression of hippocampal O-GlcNAc transferase (OGT), aimed at elevating O-GlcNAc, recapitulated this protective effect. Inhibiting OGT substrate availability negates this protective effect. Interestingly, the concurrent overexpression of hippocampal OGT alongside substrate supplementation, intended to excessively elevate O-GlcNAc, proves ineffective in affording additional protection. It even triggers a reappearance of reconsolidation resistance in the original memory. This protective role of O-GlcNAc, seemingly acting in a buffering-like manner, insulating reconsolidation from aberrant modifications within an optimal range. These data establish hippocampal O-GlcNAc as a potential target for preserving memory malleability.