Prevention of microglial activation and postoperative cognitive deficits by positive allosteric modulation of α5‐GABA _A receptors

BACKGROUND AND PURPOSE: receptors by the α5-positive allosteric modulator (α5-PAM), MP-III-022, would improve cognitive deficits after surgery. EXPERIMENTAL APPROACH: in the drinking water) was administered to mice 3 days prior to laparotomy and throughout the study. Chronologically aged mice (21-24 months old) and mice with ablation of dentate gyrus hilar somatostatin interneurons (4-5 months old), a model for hippocampal ageing, were used. Cognitive functions were assessed using a battery of behavioural tests. Immunohistochemistry and Golgi staining were used to analyse microglial activation and dendritic spine density. KEY RESULTS: In both types of mice, we found that laparotomy reduced the percentage of spontaneous alternations in the Y maze, novel object recognition, and contextual fear conditioning, while these deficits were attenuated with MP-III-022 treatment, indicating prevention or reversal of postoperative cognitive impairments. Laparotomy increased hippocampal microglial activation-associated measures and reduced dendritic spine density, and these changes were attenuated by MP-III-022 treatment. CONCLUSIONS AND IMPLICATIONS: receptors may represent a novel therapeutic strategy to prevent the development of perioperative neurocognitive deficits in aged individuals.