2. Academic Validation
  3. Sevoflurane acts as an antidepressant by suppression of GluN2D-containing NMDA receptors on interneurons

Sevoflurane acts as an antidepressant by suppression of GluN2D-containing NMDA receptors on interneurons

  • Br J Pharmacol. 2024 Sep;181(18):3483-3502. doi: 10.1111/bph.16420.
Fei Guo 1 2,  Bing Zhang 1,  Fuyi Shen 1,  Qian Li 1,  Yingcai Song 1,  Tianyu Li 1,  Yongmei Zhang 3,  Weijia Du 1,  Yuanxi Li 4,  Wei Liu 1,  Hang Cao 1,  Xianjin Zhou 1,  Yinli Zheng 2 5,  Shujia Zhu 6,  Yang Li 1 2,  Zhiqiang Liu 1 7
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Department of Anesthesiology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 Institute for Cognitive Neurodynamics, East China University of Science and Technology, Shanghai, China.
  • 5 School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
  • 6 Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
  • 7 Anesthesia and Brain Function Research Institute, Tongji University School of Medicine, Shanghai, China.
PMID: 38779864 DOI: 10.1111/bph.16420
Abstract

Background and purpose: Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects.

Experimental approach: To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole-cell patch-clamp recordings, to examine the effects on GluN1-GluN2 incorporated N-methyl-d-aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple-channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d-/-) mice were used to confirm the requirement of GluN2D for the antidepressant effects.

Key results: Repeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C- and GluN2D-containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d-/- mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect.

Conclusion and implications: Sevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression.

Keywords

GluN2D subunits; antidepressant; disinhibition; interneurons; sevoflurane.

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