Microglia-dependent PDGFB regulation of neuronal KCND2 in the hypothalamic paraventricular nucleus determines propofol anesthesia induction

Understanding the neural mechanisms underlying anesthetic-induced unconsciousness remains a central question in both anesthesia research and neuroscience. However, the role of non-neuronal components in modulating anesthetic sensitivity is poorly understood. In this study, we identify a microglia-dependent platelet-derived growth factor subunit B (PDGFB) signaling pathway that modulates propofol anesthesia sensitivity and contributes to the induction of anesthesia in mice.

We demonstrate that PDGFB signaling regulates the potassium voltage-gated channel subfamily D member 2 (KCND2) in the hypothalamic paraventricular nucleus (PVN) in mice, thereby orchestrating the excitability of PVN glutamatergic neurons (PVNGlu) and the activity of their projections to lateral hypothalamic glutamatergic neurons (LHGlu). Microglia deprivation induces PDGFB deficiency and downregulates KCND2, resulting in PVN hyperexcitability and hyperactivation of the PVN → LH arousal circuit, which contributes to resistance to anesthesia induction in mice. Our findings identified non-neuronal molecular mechanism that governs anesthetic sensitivity, complementing the classical γ-aminobutyric acid type A receptor-centric model and providing insights into the regulation of anesthesia induction.

This work was partly supported by Shenzhen Medical Research Fund (grant no. D2403012), The National Natural Science Foundation of China (grant no. NSFC82350710225 and NSFC82471250), and Shenzhen Science and Technology Program (grant no.

KQTD20200820113040070 and JCYJ20220818100615033). Present address: School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, China Present address: Department of Anesthesiology, Zhongshan hospital, Fudan University, Shanghai, China These authors contributed equally: Boxu Cao, Jiang-Jian Hu, Hongyu Yao, Yuexin Liu. Department of Medical Neuroscience and SUSTech Center for Pain Medicine, Southern University of Science and Technology School of Medicine, Shenzhen, China Boxu Cao, Jiang-Jian Hu, Hongyu Yao, Yuexin Liu, Zihan Zhu, Hao Wang, Peng Chen & Xue-Jun Song The authors declare no competing interests.

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If your intended use exceeds what is permitted by the license or if you are unable to locate the licence and re-use information, please contact the Rights and Permissions team. Cao, B., Hu, JJ., Yao, H. et al. Microglia-dependent PDGFB regulation of neuronal KCND2 in the hypothalamic paraventricular nucleus determines propofol anesthesia induction.