Metaplastic priming enables non-ionotropic NMDA receptor-mediated synaptic depotentiation in the hippocampus
Bibliographic record
Abstract
Abstract The reversal of learning-induced synaptic potentiation through depotentiation is thought to underlie forgetting and can be influenced by prior synaptic activity. Here, we evaluated how such metaplastic alterations manifest at the synaptic level. In hippocampal slices obtained from male and female mice, we artificially induced long-term potentiation (LTP) using either a temporally spaced or compressed stimulation pattern. Using a combination of electrophysiology and protein quantification approaches, we found divergent molecular pathways recruited during depotentiation of spaced and compressed LTP. Depotentiation of both forms of LTP required glutamatergic activation of the NMDA receptor (NMDAR). However, only depotentiation of spaced LTP required ionotropic NMDAR signaling, while ion flux-independent, or non-ionotropic, NMDAR signaling was necessary and sufficient for depotentiation of compressed LTP. Downstream of NMDAR signaling, AMPA receptor phosphorylation was also differentially modified during depotentiation of spaced and compressed LTP. Finally, we found that spaced but not compressed depotentiation required synaptic Arc. Together, our results reveal that the temporal pattern of prior LTP induction exerts a metaplastic influence on the molecular pathways recruited during the induction and expression of depotentiation. Our findings have important implications for the regulation of both physiological and pathological forgetting. Significance statement Synaptic depotentiation, the reversal of learning-associated synaptic potentiation, is an important mechanism of forgetting. This study uncovers how prior synaptic activity modifies the molecular mechanisms underlying depotentiation in the hippocampus in a metaplastic manner. We reveal that the mechanisms of NMDA-receptor depotentiation depend on the temporal spacing of long-term potentiation (LTP) induction. Specifically, we show that non-ionotropic NMDA receptor signaling is necessary and sufficient for the depotentiation of LTP induced using temporally compressed but not spaced patterned activity. Further, depotentiation of spaced and compressed LTP are associated with distinct downstream signaling pathways and AMPA receptor phosphorylation states during depotentiation. Our results illuminate fundamental mechanisms that govern plasticity associated with forgetting, with implications for memory preservation in disease states.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".