2. Academic Validation
  3. 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

  • Nat Neurosci. 2023 Mar 27. doi: 10.1038/s41593-023-01290-y.
Jiang-Jian Hu # 1 2,  Yuexin Liu # 1 2,  Hongyu Yao # 1 2,  Boxu Cao 1 2,  Huabao Liao 1 2,  Ruodi Yang 2,  Peng Chen 1 2,  Xue-Jun Song 3 4
Affiliations

Affiliations

  • 1 Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 2 SUSTech Center for Pain Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 3 Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen, China. songxuejun@sustech.edu.cn.
  • 4 SUSTech Center for Pain Medicine, Southern University of Science and Technology, Shenzhen, China. songxuejun@sustech.edu.cn.
  • # Contributed equally.
PMID: 36973513 DOI: 10.1038/s41593-023-01290-y
Abstract

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.

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