Microglia mediate memory dysfunction via excitatory synaptic elimination in a fracture surgery mouse model

• Published in: Journal of neuroinflammation 2024-09, Vol.21 (1), p.227-19
• Main Authors: Li, Shuming, Liu, Huan, Lv, Pin, Yao, Yu, Peng, Liangyu, Xia, Tianjiao, Yan, Chao, Ma, Zhengliang, Chen, Zhang-Peng, Zhao, Chunjie, Gu, Xiaoping
• Format: Article
• Language: English
• Subjects: Animals; Cognition disorders; Complement C3; Complement C3 - genetics; Complement C3 - metabolism; Complications and side effects; Disease Models, Animal; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Fracture fixation; Health aspects; Male; Medical research; Medicine, Experimental; Memory Disorders - etiology; Memory Disorders - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - metabolism; Microglia engulfment; Physiological aspects; Postoperative Cognitive Complications - etiology; Postoperative Cognitive Complications - metabolism; Postoperative cognitive dysfunction (POCD); Receptors, Complement - genetics; Receptors, Complement - metabolism; Risk factors; STAT3; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Synapses; Synapses - metabolism; Synapses - pathology; Synaptic loss
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-024-03216-2

Cognitive impairment is a common issue among human patients undergoing surgery, yet the neural mechanism causing this impairment remains unidentified. Surgical procedures often lead to glial cell activation and neuronal hypoexcitability, both of which are known to contribute to postoperative cognitive dysfunction (POCD). However, the role of neuron-glia crosstalk in the pathology of POCD is still unclear. Through integrated transcriptomics and proteomics analyses, we found that the complement cascades and microglial phagocytotic signaling pathways are activated in a mouse model of POCD. Following surgery, there is a significant increase in the presence of complement C3, but not C1q, in conjunction with presynaptic elements. This triggers a reduction in excitatory synapses, a decline in excitatory synaptic transmission, and subsequent memory deficits in the mouse model. By genetically knockout out C3ar1 or inhibiting p-STAT3 signaling, we successfully prevented neuronal hypoexcitability and alleviated cognitive impairment in the mouse model. Therefore, targeting the C3aR and downstream p-STAT3 signaling pathways could serve as potential therapeutic approaches for mitigating POCD.