Restoration of Extrasynaptic/Synaptic GABA(A)R-α5 Localization Improves Sevoflurane-Induced Early Memory Impairment in Aged Mice.

GABA(A) receptors containing α5-subunits (GABA(A)R-α5) cluster at both extrasynaptic and synaptic locations, interacting with the scaffold proteins radixin and gephyrin, respectively, and the re-localization of GABA(A)R-α5 influences GABAergic transmission. Here, we found that when early spatial memory deficits occurred in aged mice at 24 h after sevoflurane anesthesia, there was a re-localization of GABA(A)R-α5 that enhanced tonic inhibition and reduced the decay kinetics of miniature inhibitory postsynaptic currents in the hippocampal CA1 region. Mechanistically, increased phosphorylation of radixin at threonine 564 (Thr564) mediates the re-localization of GABA(A)R-α5. Acute treatment with the selective extrasynaptic GABA(A)R-α5 antagonist S44819 restored the GABA(A)R-α5-mediated inhibitory currents by reversing radixin phosphorylation-dependent GABA(A)R-α5 re-localization, then improved the sevoflurane-induced spatial memory impairment in aged mice. Our results suggest that the localization of GABA(A)R-α5 altered by sevoflurane is linked to unbalanced GABAergic transmission, which induces early memory impairment in aged mice. Modulating the GABA(A)R-α5 localization might be a novel strategy to improve memory after sevoflurane exposure.