C1q-mediated synapse loss by microglial phagocytosis is associated with postoperative neurocognitive disorder in mice.

Abstract

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. 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. 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. 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.