A single subanesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates this increase and ketamine’s behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell-specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrated that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst) or parvalbumin (Pvalb), but not glutamate principle neurons in the medial prefrontal cortex (mPFC). Further analysis of GABA subtypes showed that cell-specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.

中文翻译：

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GABA interneurons是氯胺酮快速抗抑郁作用的细胞触发

亚麻醉剂量的氯胺酮（一种NMDA受体（NMDAR）拮抗剂）可以在抑郁症患者中产生快速而持续的抗抑郁作用，从而满足了对情绪障碍治疗的主要未满足需求。氯胺酮会在额叶前皮质中迅速增加细胞外谷氨酸和突触的形成，但尚未发现引发这种增加和氯胺酮行为行为的初始细胞触发。为了解决这个问题，我们使用了病毒shRNA和条件突变的组合，以产生细胞特异性的敲除或缺失的关键NMDAR亚基GluN2B，这与氯胺酮的作用有关。结果表明，氯胺酮的抗抑郁作用被GluN2B-NMDAR对GABA（Gad1）中神经元以及表达生长抑素（Sst）或小白蛋白（Pvalb），但内侧前额叶皮层（mPFC）中没有谷氨酸主要神经元。对GABA亚型的进一步分析表明，Sst中神经元中的细胞特异性敲除或GluN2B的缺失阻断或阻断了氯胺酮的抗抑郁作用，并揭示了性别特异性差异，其与mPFC原理神经元上的兴奋性突触后电流相关。这些发现表明，GABA Interneurons上的GluN2B-NMDARs是氯胺酮快速抗抑郁作用的最初细胞触发，并显示了针对GluN2B调节的性别特异性适应机制。