P4‐228: O‐GlcNAc regulation of hippocampal synaptic plasticity in wild type and 3xTg‐AD mice
Bibliographic record
Abstract
O-linked N-acetylglucosamine (O-GlcNAc) is a cytosolic and nuclear carbohydrate post-translational modification, but its functions are little understood. We recently reported uniquely extensive O-GlcNAc modification at neuronal synapses, particularly on proteins that regulate distribution of synaptic vesicle pools. We examined potential roles for O-GlcNAc in mouse hippocampal synaptic transmission and plasticity through in vivo pharmacological modulation of O-GlcNAc and analysis of biochemical signaling, electrophysiology, and behavioral learning/memory tests. Pharmacological elevation or reduction of O-GlcNAc levels had no effect on Schaffer collateral CA1 basal hippocampal synaptic transmission. However, in vivo elevation of O-GlcNAc levels enhanced long term potentiation (LTP), an electrophysiological correlate to some forms of learning/memory. Reciprocally, pharmacological reduction of O-GlcNAc levels blocked LTP. Elevated O-GlcNAc altered several phosphorylation events linked to synaptic plasticity, including increased phosphorylation of Synapsin I/II at several sites linked to enhanced availability of synaptic vesicles for release, as well as increased activation specific phosphorylation of Erk 1/2. Hippocampal dependent spatial learning in mice led to increased O-GlcNAc levels, consistent with a potential in vivo role for dynamic O-GlcNAc in learning related synaptic plasticity. Reduced O-GlcNAc has been observed in human Alzheimer's disease. In the Alzheimer's mouse model 3XTg-AD, we observed reduced O-GlcNAc on specific synaptic proteins, including synapsin I. Pharmacological elevation of O-GlcNAc in 9 month 3XTg-AD mice normalized defects in cognitive hippocampal dependent spatial learning, and this was accompanied by modulation of several LTP linked phosphoryaltion events. Thus, O-GlcNAc is a novel regulatory signaling component of neuronal synapses, with specific roles in plasticity that involve interplay with phosphorylation, and may represent a novel therapeutic target for improvement of synaptic deficits and memory in Alzheimer's disease.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".