Microglia participate in postoperative cognitive dysfunction by mediating the loss of inhibitory synapse through the complement pathway. (6th February 2023) - Tan, Xiaoxiang
Highlights: Exploring the pathogenesis of postoperative cognitive dysfunction is essential to improve the prognosis of patients. The establishment of POCD model in aged mice and related behavioral experiments are more relevant to clinical treatment and have more clinical significance. The combination of neuroinflammation caused by microglia and complement pathway plays an important role in the destruction of neural network leading to cognitive dysfunction. The E/I imbalance mediated by the loss of inhibitory synapses is a new mechanism and discovery that leads to cognitive dysfunction. This finding provides an idea for future research on whether neurons with inhibitory function can be regulated to improve cognitive function. Abstract: Background: Elderly patients after surgery are prone to cognitive decline known as postoperative cognitive dysfunction (POCD). Several studies have shown that the microglial activation and the increase of complement protein expression in hippocampus induced by surgery may be related to the pathogenesis of POCD. The purpose of this study was to determine whether microglia and complement system were involved in cognitive dysfunction in aged mice. Methods: The POCD model was established by exploratory laparotomy in 15-month-old male C57BL/6J mice and animal behavioral tests were performed to test hippocampal-dependent memory capacity. Minocycline was used to suppress the activation of microglia, and complement 3 receptor inhibitor was used to suppress the association between microglia and complement 3. Western blot and immunofluorescence were used to detect the microglial activation, complement protein, and synaptic protein expressions. Results: Operation induced hippocampal-dependent memory impairment ( P < 0.01), which was accompanied by microglial activation ( P < 0.01). There was also a significant reduction in inhibitory synaptic protein expression in the hippocampus of mice in the surgery group ( P < 0.01). However, minocycline, a microglia inhibitor, rescued all the above changes. In addition, C3RI intervention inhibited the phagocytosis of inhibitory synapses by microglia ( P < 0.05) and improved the cognitive function of mice ( P < 0.01). Conclusion: Microglia participate in postoperative cognitive dysfunction by mediating inhibitory synaptic loss through the complement pathway.