Sevoflurane alters α5β3GABAA receptor trafficking via calcium/calmodulin-dependent protein kinase II-dependent β3 subunit phosphorylation to produce cognitive impairment in aged mice

Background Sevoflurane increases surface expression of α5 subunit-containing γ-aminobutyric acid type A receptors (GABA A R-α5) and tonic currents in the hippocampus, contributing to postoperative memory decline. We investigated sevoflurane modulation of the phosphorylation of the β3 subunit which co-assembles with α5 subunits following Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activation to alter receptor trafficking and exacerbate cognitive dysfunction. Methods Aged C57BL/6J mice and primary hippocampal neurones were exposed to 4 vol% sevoflurane for 2 h (Sev group). Cultured neurones were transfected with a phospho-null β3 subunit (S408/409A) generated by site-directed mutagenesis. Immunoblot analysis, immunofluorescence, Ca 2+ imaging, whole-cell patch-clamp electrophysiological recording, pharmacological interventions, and behavioural tests were used. Results Sevoflurane triggered CaMKII-mediated phosphorylation at β3-S408/409, suppressing receptor internalisation and increasing surface accumulation of α5β3GABA A Rs (Sev vs control; P