Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
J Neuroinflammation. 2024 Sep 16;21(1):227. 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.
认知障碍是接受手术的人类患者中常见的问题，但导致这种障碍的神经机制仍不清楚。手术程序通常会导致神经胶质细胞激活和神经元兴奋性降低，这两者都已知会导致术后认知功能障碍（POCD）。然而，神经元-神经胶质细胞相互作用在 POCD 病理中的作用仍不清楚。通过整合转录组学和蛋白质组学分析，我们发现补体级联反应和小胶质细胞吞噬信号通路在 POCD 的小鼠模型中被激活。手术后，与突触前元件一起，补体 C3 而非 C1q 的存在显著增加。这导致兴奋性突触减少、兴奋性突触传递下降，以及随后在小鼠模型中出现记忆缺陷。通过基因敲除 C3ar1 或抑制 p-STAT3 信号，我们成功地防止了小鼠模型中的神经元兴奋性降低和认知障碍。因此，靶向 C3aR 和下游 p-STAT3 信号通路可能是减轻 POCD 的潜在治疗方法。
