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
  • 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.
Products