2. Academic Validation
  3. Microglia mediate memory dysfunction via excitatory synaptic elimination in a fracture surgery mouse model

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

  • J Neuroinflammation. 2024 Sep 16;21(1):227. doi: 10.1186/s12974-024-03216-2.
Shuming Li # 1,  Huan Liu # 2,  Pin Lv 3,  Yu Yao 2,  Liangyu Peng 2,  Tianjiao Xia 4,  Chao Yan 5,  Zhengliang Ma 2,  Zhang-Peng Chen 6,  Chunjie Zhao 7,  Xiaoping Gu 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. lishuming0703@126.com.
  • 2 Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 3 Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 4 Medical School, Nanjing University, Nanjing, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
  • 6 Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. xiaopengczp@163.com.
  • 7 Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing, China. zhaocj@seu.edu.cn.
  • 8 Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. xiaopinggu@nju.edu.cn.
  • # Contributed equally.
PMID: 39285282 DOI: 10.1186/s12974-024-03216-2
Abstract

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.

Keywords

Complement C3; Microglia engulfment; Postoperative cognitive dysfunction (POCD); STAT3; Synaptic loss.

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