Abstract：
OBJECTIVE: 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.
METHODS: 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.
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.
CONCLUSIONS: 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.
METHODS: 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.
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.
CONCLUSIONS: 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.
摘要：
目标：七氟醚，一种常用的吸入麻醉剂，以其良好的安全性和快速起效和抵消而闻名，尚未被彻底研究作为抑郁症的潜在治疗方法。在这项研究中,我们揭示了七氟醚提供持久抗抑郁作用的机制.
方法：为了评估七氟醚的抗抑郁作用，进行了行为测试，以及体外和离体全细胞膜片钳记录，检查对内侧前额叶皮质（mPFC）中GluN1-GluN2掺入N-甲基-d-天冬氨酸（NMDA）受体（NMDARs）和神经元电路的影响。在自由移动的小鼠中进行多通道电生理学以评估七氟醚对神经元活动的影响,和GluN2D敲除(grin2d-/-)小鼠用于确认GluN2D对抗抑郁作用的需求。
结果：反复暴露于亚麻醉剂量的七氟烷产生持续的抗抑郁作用，持续2周。七氟醚优先抑制含有GluN2C和GluN2D的NMDARs，导致中间神经元活动减少。相比之下,七氟醚增加mPFC锥体神经元的动作电位（AP）放电和减少自发抑制性突触后电流（sIPSC），表现出抑制作用。这些作用在grin2d-/-小鼠中不存在，GluN2D的药物阻断和基因敲除消除了七氟醚的抗抑郁作用，这表明GluN2D对其抗抑郁作用至关重要。
结论：七氟醚直接靶向GluN2D，导致中间神经元活性的特定降低和随后的锥体神经元的去抑制，这可能是其抗抑郁作用的基础。靶向GluN2D亚基有望成为治疗抑郁症的潜在治疗策略。
方法：为了评估七氟醚的抗抑郁作用，进行了行为测试，以及体外和离体全细胞膜片钳记录，检查对内侧前额叶皮质（mPFC）中GluN1-GluN2掺入N-甲基-d-天冬氨酸（NMDA）受体（NMDARs）和神经元电路的影响。在自由移动的小鼠中进行多通道电生理学以评估七氟醚对神经元活动的影响,和GluN2D敲除(grin2d-/-)小鼠用于确认GluN2D对抗抑郁作用的需求。
结果：反复暴露于亚麻醉剂量的七氟烷产生持续的抗抑郁作用，持续2周。七氟醚优先抑制含有GluN2C和GluN2D的NMDARs，导致中间神经元活动减少。相比之下,七氟醚增加mPFC锥体神经元的动作电位（AP）放电和减少自发抑制性突触后电流（sIPSC），表现出抑制作用。这些作用在grin2d-/-小鼠中不存在，GluN2D的药物阻断和基因敲除消除了七氟醚的抗抑郁作用，这表明GluN2D对其抗抑郁作用至关重要。
结论：七氟醚直接靶向GluN2D，导致中间神经元活性的特定降低和随后的锥体神经元的去抑制，这可能是其抗抑郁作用的基础。靶向GluN2D亚基有望成为治疗抑郁症的潜在治疗策略。
