Restoration of Extrasynaptic/Synaptic GABAR-α5 Localization Improves Sevoflurane-Induced Early Memory Impairment in Aged Mice.

GABA receptors containing α5-subunits (GABAR-α5) cluster at both extrasynaptic and synaptic locations, interacting with the scaffold proteins radixin and gephyrin, respectively, and the re-localization of GABAR-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 GABAR-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 GABAR-α5. Acute treatment with the selective extrasynaptic GABAR-α5 antagonist S44819 restored the GABAR-α5-mediated inhibitory currents by reversing radixin phosphorylation-dependent GABAR-α5 re-localization, then improved the sevoflurane-induced spatial memory impairment in aged mice. Our results suggest that the localization of GABAR-α5 altered by sevoflurane is linked to unbalanced GABAergic transmission, which induces early memory impairment in aged mice. Modulating the GABAR-α5 localization might be a novel strategy to improve memory after sevoflurane exposure.