Cichon Joseph, Joseph Thomas T, Lu Xinguo, Wasilczuk Andrzej Z, Kelz Max B, Mennerick Steven J, Zorumski Charles F, Nagele Peter
Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Commun. 2025 Apr 3;16(1):2999. doi: 10.1038/s41467-025-57951-y.
Nitrous oxide (NO) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled NO induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. NO-induced L5 activation rescues a stress-associated hypoactivity state, persists following exposure, and is necessary for its antidepressant-like activity. Although NMDA-receptor antagonism is believed to be a primary mechanism of action for NO, L5 neurons activate even when NMDA-receptor function is attenuated through both pharmacological and genetic approaches. By examining different molecular and circuit targets, we identify NO-induced inhibition of calcium-sensitive potassium (SK2) channels as a key molecular interaction responsible for driving specific L5 activity along with ensuing antidepressant-like effects. These results suggest that NO-induced L5 activation is crucial for its fast antidepressant action and this effect involves novel and specific molecular actions in distinct cortical cell types.
一氧化二氮（NO）能诱导快速且持久的抗抑郁作用。介导这一过程的细胞和神经回路机制尚不清楚。在此，我们发现单次吸入NO能快速且特异性地激活暴露于慢性应激条件下的啮齿动物扣带回皮层第V层（L5）锥体神经元。NO诱导的L5激活可挽救与应激相关的活动减退状态，在暴露后持续存在，且是其抗抑郁样活性所必需的。尽管NMDA受体拮抗作用被认为是NO的主要作用机制，但即使通过药理学和遗传学方法使NMDA受体功能减弱，L5神经元仍会激活。通过研究不同的分子和神经回路靶点，我们确定NO诱导的对钙敏感钾通道（SK2）的抑制是驱动特定L5活动以及随之而来的抗抑郁样作用的关键分子相互作用。这些结果表明，NO诱导的L5激活对其快速抗抑郁作用至关重要，且这种作用涉及不同皮层细胞类型中新颖且特异性的分子作用。
