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Updated: May 9, 2026
A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
C1q-mediated synapse loss by microglial phagocytosis is associated with postoperative neurocognitive disorder in mice
Jingjing Lv1, Liang Yao2, Lili Tang2
1Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, China; Department of Anesthesiology, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, China.
Background:
Perioperative neurocognitive disorders (PNDs) are common complications in elderly surgical patients. Possible pathogenic mechanisms for the development of PNDs include loss of synaptic connections mediated by microglial activation, although the precise mechanisms are not fully understood.
Methods:
Male and female C57BL/6J or male Cx3cr1-CreERT2 mice, aged 8-12 weeks, were subjected to aseptic tibial fracture surgery, and cognitive tests were carried out 3 days after surgery. Through a combination of bulk RNA sequencing, Western immunoblotting, immunofluorescence, and Golgi staining of the hippocampus, we investigated the role of complement C1q in activating microglia and phagocytosing synaptic connections in the pathogenesis of postoperative neurocognitive disorder.
Results:
Postoperative mice displayed memory deficits in both the Y-maze (P<0.001) and the trace fear conditioning (TFC) paradigms (P=0.002); these memory deficits were associated with increased microglial activation, complement C1q upregulation, classical complement pathway transcriptomic upregulation, and synapse loss (all P<0.05). After surgery, there was a ∼2-fold increase in colocalisation of C1qa with Homer1 (excitatory) or gephyrin (inhibitory) synaptic proteins in microglia (P<0.001). Postoperative memory decline and synapse loss did not occur after treatment with microglial activity inhibitor minocycline, after exposure to C1q neutralising antibody JL-1, or after C1q depletion from CA1 microglia. Activation of NF-κB was correlated with elevated levels of complement C1q in models, and selective inhibition of NF-κB activation with pyrrolidinedithiocarbamate ammonium (PDTC) attenuated the surgery-induced elevation of C1q and improved cognitive function.
Conclusions:
The results demonstrate that hippocampal microglia prune both excitatory and inhibitory synapses in a C1q-dependent manner, contributing to postoperative synapse loss and cognitive dysfunction. Targeting C1q and NF-κB activation could be a promising therapeutic intervention to ameliorate perioperative neurocognitive disorders.
Insights
Surgery can cause memory loss in elderly patients due to microglial activation and synapse loss. Targeting complement C1q and NF-κB pathways may prevent these postoperative neurocognitive disorders.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Perioperative neurocognitive disorders (PNDs) are frequent in elderly surgical patients.
- Microglial activation and synaptic loss are implicated in PNDs, but mechanisms remain unclear.
Purpose of the Study:
- Investigate the role of complement C1q in microglial activation and synapse loss in postoperative neurocognitive disorder.
- Explore potential therapeutic targets for PNDs.
Main Methods:
- Utilized a mouse model of tibial fracture surgery.
- Employed bulk RNA sequencing, Western immunoblotting, immunofluorescence, and Golgi staining.
- Assessed cognitive function using Y-maze and trace fear conditioning tests.
Main Results:
- Postoperative mice showed memory deficits, increased microglial activation, complement C1q upregulation, and synapse loss.
- Complement C1q colocalized with synaptic proteins in microglia.
- Inhibition of C1q or NF-κB activation ameliorated cognitive decline and synapse loss.
Conclusions:
- Hippocampal microglia prune synapses in a C1q-dependent manner, causing postoperative cognitive dysfunction.
- Targeting C1q and NF-κB presents a potential therapeutic strategy for PNDs.
