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Updated: Jun 13, 2025
A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration
Published on: February 27, 2018
Microglia mediate memory dysfunction via excitatory synaptic elimination in a fracture surgery mouse model
Shuming Li1, Huan Liu2, Pin Lv3
1Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. lishuming0703@126.com.
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.
Insights
Surgery can cause cognitive impairment due to activated glial cells and neuronal hypoexcitability. Targeting complement C3aR and p-STAT3 pathways may prevent postoperative cognitive dysfunction (POCD).
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Postoperative cognitive dysfunction (POCD) is a common complication following surgery, with unclear underlying neural mechanisms.
- Surgical stress activates glial cells and causes neuronal hypoexcitability, contributing to POCD.
- The role of neuron-glia interactions in POCD pathology requires further elucidation.
Purpose of the Study:
- To investigate the neural mechanisms of POCD by examining neuron-glia crosstalk.
- To identify specific molecular pathways involved in surgery-induced cognitive deficits.
Main Methods:
- Integrated transcriptomics and proteomics analyses in a mouse model of POCD.
- Immunohistochemical analysis to detect complement C3 localization.
- Genetic knockout of C3ar1 and inhibition of p-STAT3 signaling.
Main Results:
- Surgery activated complement cascades and microglial phagocytotic pathways in the POCD mouse model.
- Increased complement C3 associated with presynaptic elements led to reduced excitatory synapses and impaired synaptic transmission.
- Genetic knockout of C3ar1 or p-STAT3 inhibition prevented neuronal hypoexcitability and alleviated memory deficits.
Conclusions:
- The complement C3a-C3aR signaling pathway, coupled with p-STAT3, plays a critical role in POCD pathogenesis.
- Targeting the C3aR and p-STAT3 signaling pathways offers potential therapeutic strategies for mitigating POCD.
