Disruption of the GABAergic system contributes to the development of perioperative neurocognitive disorders after anesthesia and surgery in aged mice

Aims: Perioperative neurocognitive disorders (PND) are associated with cognitive impairment in the preoperative or postoperative period, and neuroinflammation is thought to be the most important mechanisms especially during the postoperative period. The GABAergic system is easily disrupted by neuroinflammation. This study investigated the impact of the GABAergic system on PND after anesthesia and surgery.

Methods: An animal model of laparotomy with inhalation anesthesia in 16-month-old mice was addressed. Effects of the GABAergic system were assessed using biochemical analysis. Pharmacological blocking of α5GABA_A Rs or P38 mitogen-activated protein kinase (MAPK) were applied to investigate the effects of the GABAergic system.

Results: After laparotomy, the hippocampus-dependent memory and long-term potentiation were impaired, the levels of IL-6, IL-1β and TNF-α up-regulated in the hippocampus, the concentration of GABA decreased, and the protein levels of the surface α5GABA_A Rs up-regulated. Pharmacological blocking of α5GABA_A Rs with L655,708 alleviated laparotomy induced cognitive deficits. Further studies found that the p38 MAPK signaling pathway was involved and pharmacological blocking with SB203,580 alleviated memory dysfunctions.

Conclusions: Anesthesia and surgery caused neuroinflammation in the hippocampus, which consequently disrupted the GABAergic system, increased the expressions of surface α5GABA_A Rs especially through the p38 MAPK signaling pathway, and eventually led to hippocampus-dependent memory dysfunctions.