Internalization of GluA2 and the underlying mechanisms of cognitive decline in aged rats following surgery and prolonged exposure to sevoflurane

• Prolonged exposure (2 h) of 1.5 MAC sevoflurane execerbated cognitive decline after surgery.
• 2 h of sevoflurane exposure worsened the decline of cell surface AMAPR GluR2 subunit.
• 2 h of sevoflurane exposure reduced the PI3K-AMPAR GluR2 complex formation.
• 2 h of sevoflurane exposure promoted MEF2-Arc pathway long time after surgery.
• 2 h of sevoflurane exposure impaired the spines in hippocampus after surgery.

BackgroundWe revealed that a high concentration of sevoflurane exacerbated cognitive impairment in aged rats, and the inhibition of GluA2 subunit internalization facilitated neuroprotection after a cerebral ischemic injury. However, the trafficking of GluA2 in POCD and its underlying mechanism are not clear. We thus detected the effects of sevoflurane for different inhalation durations on postoperative cognitive function and investigated the role of GluA2 subunit trafficking in this process.MethodsA rat model of orthopedic surgery was performed with different durations of 1.5 MAC sevoflurane inhalation. Cognitive function was evaluated by manipulating the Y maze and fear conditioning tests for 7 days after experiments. Western blot, ELISA and coimmunoprecipitation were applied to analyze GluA2 internalization, PI3K expression and its activity, as well as alterations to the MEF2-Arc pathway in the hippocampus. Neuron apoptosis and the spine morphology in the hippocampus were also observed.ResultsWe found that neuron apoptosis and GluA2 internalization increased following surgery and 1.5 MAC sevoflurane inhalation for 2 h, possibly due to the decrease of the PI3K-GluA2 complex and PI3K activity in the hippocampus after prolonged 1.5 MAC sevoflurane inhalation. We also observed that the MEF2-Arc pathway contributed to long-term cognitive function, which also impaired the spinal morphology after 1.5 MAC sevoflurane inhalation for 2 h.ConclusionThe above results suggest that 1.5 MAC sevoflurane inhalation for 2 h potentiated surgery-impaired cognitive function and that the inhibition of PI3K-AMPAR GluA2 as well as activation of the MEF2-Arc signal pathway contributes to different stages of POCD.