Emergence of consciousness from anesthesia through ubiquitin degradation of KCC2 in the ventral posteromedial nucleus of the thalamus
Emergence of consciousness from anesthesia through ubiquitin degradation of KCC2 in the ventral posteromedial nucleus of the thalamus
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DOI：
10.1038/s41593-023-01290-y
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发表时间：
2023-03
影响因子：
25
通讯作者：
Jiang-Jian Hu;Yuexin Liu;H. Yao;Boxu Cao;Huabao Liao;Ruodi Yang;Peng Chen;Xue-Jun Song
中科院分区：
文献类型：
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作者：
Jiang-Jian Hu;Yuexin Liu;H. Yao;Boxu Cao;Huabao Liao;Ruodi Yang;Peng Chen;Xue-Jun Song
意识从麻醉中苏醒，曾经被认为是一个被动的过程，现在被认为是一个主动的、可控的过程。在本研究中，我们在小鼠身上显示，当不同麻醉剂迫使大脑进入最低反应状态时，腹后内侧核K+/Cl−协同转运体2(KCC2)的快速下调是大脑恢复意识的常见机制。泛素-蛋白酶体的降解是KCC2下调的原因，该下调是由泛素连接酶FBXL4驱动的。KCC2在Thr1007处的磷酸化促进了KCC2和FBXL4之间的相互作用。KCC2下调导致γ-氨基丁酸A型受体介导的去抑制，使室隔核神经元兴奋性加速恢复和意识从麻醉抑制中苏醒。这种恢复的途径是一个活跃的过程，不依赖于麻醉剂的选择。本研究表明，VPM中KCC2的泛素降解是从麻醉中苏醒的重要中间步骤。
The emergence of consciousness from anesthesia, once assumed to be a passive process, is now considered as an active and controllable process. In the present study, we show in mice that, when the brain is forced into a minimum responsive state by diverse anesthetics, a rapid downregulation of K+/Cl−cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) serves as a common mechanism by which the brain regains consciousness. Ubiquitin-proteasomal degradation is responsible for KCC2 downregulation, which is driven by ubiquitin ligase Fbxl4. Phosphorylation of KCC2 at Thr1007 promotes interaction between KCC2 and Fbxl4. KCC2 downregulation leads to γ-aminobutyric acid type A receptor-mediated disinhibition, enabling accelerated recovery of VPM neuron excitability and emergence of consciousness from anesthetic inhibition. This pathway to recovery is an active process and occurs independent of anesthetic choice. The present study demonstrates that ubiquitin degradation of KCC2 in the VPM is an important intermediate step en route to emergence of consciousness from anesthesia.