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Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3β activation in young mice
Guorong Tao1, Jie Zhang, Lei Zhang
1From the Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China (G.T.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R China (J.Z.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, P. R. China (L.Z.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts (Y.D., Y.Z., Z.X.); Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China (B.Y.); and Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (G.C., D.J.C.).
Insights
Sevoflurane anesthesia in young mice induced Tau phosphorylation and cognitive impairment. These effects were mediated by glycogen synthase kinase 3β activation and were absent in Tau knockout mice.
Area of Science:
- Neuroscience
- Anesthesiology
- Molecular Biology
Background:
- Pediatric anesthesia and surgery increase the risk of cognitive impairment.
- Sevoflurane is a common anesthetic in children.
- Tau phosphorylation is linked to cognitive dysfunction.
Purpose of the Study:
- To investigate the effects of sevoflurane on Tau phosphorylation in young mice.
- To explore the underlying mechanisms of sevoflurane-induced cognitive impairment.
Main Methods:
- Young wild-type and Tau knockout mice were exposed to sevoflurane.
- Assessed Tau phosphorylation, related kinases/phosphatase, interleukin-6, and postsynaptic density protein-95 levels in the hippocampus.
- Evaluated cognitive function in treated and control mice.
Main Results:
- Sevoflurane induced Tau phosphorylation and activated glycogen synthase kinase 3β in wild-type mice.
- Sevoflurane decreased postsynaptic density protein-95 levels and caused cognitive impairment.
- Lithium inhibited sevoflurane-induced effects; Tau knockout mice showed no impairment.
Conclusions:
- Sevoflurane triggers Tau phosphorylation, glycogen synthase kinase 3β activation, and cognitive deficits in young mice.
- Interleukin-6 and postsynaptic density protein-95 levels are implicated in these effects.
- Future research will clarify the cascade of these sevoflurane-induced neurological changes.
Background:
Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane is a commonly used anesthetic in children. Tau phosphorylation contributes to cognitive dysfunction. The authors therefore assessed the effects of sevoflurane on Tau phosphorylation and the underlying mechanisms in young mice.
Methods:
Six-day-old wild-type and Tau knockout mice were exposed to sevoflurane. The authors determined the effects of sevoflurane anesthesia on Tau phosphorylation, levels of the kinases and phosphatase related to Tau phosphorylation, interleukin-6 and postsynaptic density protein-95 in hippocampus, and cognitive function in both young wild-type and Tau knockout mice.
Results:
Anesthesia with 3% sevoflurane 2 h daily for 3 days induced Tau phosphorylation (257 vs. 100%, P = 0.0025, n = 6) and enhanced activation of glycogen synthase kinase 3β, which is the kinase related to Tau phosphorylation in the hippocampus of postnatal day-8 wild-type mice. The sevoflurane anesthesia decreased hippocampus postsynaptic density protein-95 levels and induced cognitive impairment in the postnatal day-31 mice. Glycogen synthase kinase 3β inhibitor lithium inhibited the sevoflurane-induced glycogen synthase kinase 3β activation, Tau phosphorylation, increased levels of interleukin-6, and cognitive impairment in the wild-type young mice. Finally, the sevoflurane anesthesia did not induce an increase in interleukin-6 levels, reduction in postsynaptic density protein-95 levels in hippocampus, or cognitive impairment in Tau knockout young mice.
Conclusions:
These data suggested that sevoflurane induced Tau phosphorylation, glycogen synthase kinase 3β activation, increase in interleukin-6 and reduction in postsynaptic density protein-95 levels in hippocampus of young mice, and cognitive impairment in the mice. Future studies will dissect the cascade relation of these effects.
