Cognitive dysfunction induced by ketamine and xylazine anesthesia is associated with tau hyperphosphorylation following CaMKII activation
Bibliographic record
Abstract
Abstract Background Recent studies indicate that anesthesia is likely to contribute to the development and exacerbation of neurodegenerative disorders such as Alzheimer’s disease (AD). Although it is well established that tau hyperphosphorylation is induced following anesthesia and is a major neuropathological hallmark of AD, the relationship between tau pathology and post‐anesthetic memory impairment remains unclear. The main objective of this study was to determine if tau phosphorylation and cognitive function in mice are altered by ketamine/xylazine, a common regimen of general anesthesia used in animal research and veterinary medicine. Method Mice were anesthetized with intraperitoneal (ip) injections of ketamine/xylazine, and tau phosphorylation was evaluated in hypothermic and normothermic conditions 1 h and 6 h following anesthesia. To delineate the mechanisms underlying tau phosphorylation, we assessed by electrophoresis the levels of phosphorylation and activity of various kinases and phosphatases known to regulate tau phosphorylation. Post‐anesthetic memory deficits induced by ketamine/xylazine were examined in two different behavioral paradigms, the Y maze and passive avoidance task (PAT). Result Ketamine and xylazine have an additive and rapid effect on the phosphorylated state of tau. Mechanistically, we found that activation of calmodulin‐dependent protein kinase II (CaMKII) is the major upstream molecular event leading to tau hyperphosphorylation following ketamine/xylazine anesthesia in mice. Moreover, we observed that intracerebroventricular (icv) injection of the selective CaMKII inhibitor KN93 attenuated tau hyperphosphorylation and post‐anesthetic memory deficits induced by ketamine/xylazine in the Y maze and PAT paradigms. Ketamine/xylazine also had a marked impact on many other key molecular signaling pathways involving ERK, GSK3, STEP, Akt, Src, and the GluN2B subunit of the NMDAR. Conclusion This study demonstrates that cognitive impairments induced by ketamine/xylazine exposure are associated with tau hyperphosphorylation mainly through CaMKII activation in mice. Our results also revealed major molecular and cognitive effects of the widely used anesthetic ketamine/xylazine in animal research and veterinary practice, and call for high precaution and careful monitoring when used in laboratory animal settings to avoid artifactual results.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".