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.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Br J Pharmacol. 2024 Sep;181(18):3483-3502. doi: 10.1111/bph.16420. Epub 2024 May 23.
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.
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.
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.
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.
七氟醚是一种常用的吸入麻醉剂，具有良好的安全性和快速起效与消退的特点，但其作为一种潜在的抗抑郁治疗方法尚未得到充分研究。在这项研究中，我们揭示了七氟醚产生持久抗抑郁作用的机制。
为了评估七氟醚的抗抑郁作用，我们进行了行为学测试，并进行了体外和离体全细胞膜片钳记录，以研究其对中前额皮质（mPFC）中 GluN1-GluN2 整合的 N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）和神经元回路的影响。在自由活动的小鼠中进行多通道电生理学研究，以评估七氟醚对神经元活动的影响，并使用 GluN2D 敲除（grin2d）小鼠来确认 GluN2D 对其抗抑郁作用的必要性。
重复暴露于亚麻醉剂量的七氟醚可产生持续长达 2 周的抗抑郁作用。七氟醚优先抑制含有 GluN2C 和 GluN2D 的 NMDAR，导致中间神经元活动减少。相比之下，七氟醚增加了 mPFC 锥体神经元的动作电位（AP）放电并减少了自发性抑制性突触后电流（sIPSC），表现出一种去抑制作用。这些作用在 grin2d 小鼠中不存在，而 GluN2D 的药理学阻断和基因敲除均消除了七氟醚的抗抑郁作用，表明 GluN2D 是其抗抑郁作用所必需的。
七氟醚直接靶向 GluN2D，导致中间神经元活动的特异性减少，随后锥体神经元去抑制，这可能是其抗抑郁作用的基础。靶向 GluN2D 亚基可能成为治疗抑郁症的一种有潜力的治疗策略。
