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

Background and Purpose Long‐lasting cognitive deficits after surgery in aged individuals, referred to as perioperative neurocognitive disorder (NCD), are a significant public health concern. Such postoperative cognitive deficits are dependent on the presence of microglia in the brain, which, when activated, trigger neuroinflammation. The objective of our study was to determine whether modulation of α5‐GABA A receptors by the α5‐positive allosteric modulator (α5‐PAM), MP‐III‐022, would improve cognitive deficits after surgery. Experimental Approach MP‐III‐022 (1 mg·kg −1 ·day −1 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 The α5‐PAM, MP‐III‐022, essentially abolished laparotomy‐induced cognitive deficits and structural alterations. Positive allosteric modulation of α5‐GABA A receptors may represent a novel therapeutic strategy to prevent the development of perioperative neurocognitive deficits in aged individuals.