Dexmedetomidine rescues sleep loss-induced cognitive deficits by suppressing microglia-mediated synaptic elimination via a complement C3-C3aR pathway
作者单位：the First Affiliated Hospital of Xi'an Jiaotong University 西安交通大学第一附属医院脑科学研究中心
会议名称：《中国睡眠研究会第十四届全国学术年会》
会议日期：2022年
学科分类：1002[医学-临床医学] 100217[医学-麻醉学] 10[医学]
摘 要：Objective: Dexmedetomidine(DEX) as an anesthetic adjunct for patient sedation and general anesthesia is beneficial for improving outcomes of postoperative cognitive function. However, the effect of DEX on sleep deprivation-induced cognitive deficits and the underlying mechanism remains unclear. Methods: In the present study, C57BL/6 mice were sleep-deprived for 20 h per day for 7 consecutive days and DEX was intravenously injected at a dose of 100 μg kg-1 two times per day. Results: Using the chronic sleep restriction(CSR) model, we found that CSR mice displayed cognitive deficits, and these impairments were correlated with aberrant microglial activation and increased CD68+ phagosomes in microglial somata containing the postsynaptic protein PSD95. Also, our results showed that complement C3 secreted from astrocytes and microglial C3a receptor(C3aR) were unregulated in CSR mice. The C3-C3aR pathway mediates synaptic elimination in CSR-induced cognitive deficits. Interestingly, cognitive deficits were improved in DEX-treated CSR mice. This could be caused by DEX inhibiting the release of complement C3 from astrocytes, which acts on the microglial C3aR to influence microglia elimination via activating astrocytic α 2A adrenergic receptors in the hippocampus. Furthermore, systemic blockade of C3-C3aR signaling and intrahippocampal injection of α 2A adrenoceptor antagonist attenuated CSR-induced synaptic elimination and cognitive deficits. Conclusion: Our results indicate that DEX reverses cognitive deficits by suppressing microglia-mediated synaptic elimination via the C3-C3aR pathway following sleep deprivation. This study provides a new virtue for the patient-controlled sleep therapy with DEX and identifies a potential mechanism underlying cognitive impairment in patients recovering from sleep loss.