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Cognitive dysfunction induced by ketamine and xylazine anesthesia is associated with tau hyperphosphorylation following CaMKII activation
Author(s) -
Brouillette Jonathan,
Hector Audrey,
McAnulty Christina,
PicheLemieux MaudeEloise,
AlvesPires Claire,
BuéeScherrer Valérie,
Buee Luc
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041045
Subject(s) - xylazine , ketamine , hyperphosphorylation , anesthetic , phosphorylation , pharmacology , medicine , anesthesia , morris water navigation task , intraperitoneal injection , neuroscience , endocrinology , hippocampus , chemistry , psychology , biochemistry
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.