Major depressive disorder (MDD) is a complex and heterogeneous mood disorder, making it difficult to develop a generalized, pharmacological therapy that is effective for all who suffer from MDD. Through the fortuitous discovery of N-methyl-D-aspartate receptor (NMDAR) antagonists as effective antidepressants, we have gained key insights into how antidepressant effects can be produced at the circuit and molecular levels. NMDAR antagonists act as rapid-acting antidepressants such that relief from depressive symptoms occurs within hours of a single injection. The mode of action of NMDAR antagonists seemingly relies on their ability to activate protein-synthesis-dependent homeostatic mechanisms that restore top-down excitatory connections. Recent evidence suggests that NMDAR antagonists relieve depressive symptoms by forming new synapses resulting in increased excitatory drive. This event requires the mammalian target of rapamycin complex 1 (mTORC1), a signaling pathway that regulates synaptic protein synthesis. Herein, we review critical studies that shed light on the action of NMDAR antagonists as rapid-acting antidepressants and how they engage a neuron's or neural network's homeostatic mechanisms to self-correct. Recent studies notably demonstrate that a shift in γ-amino-butyric acid receptor B (GABA_BR) function, from inhibitory to excitatory, is required for mTORC1-dependent translation with NMDAR antagonists. Finally, we discuss how GABA_BR activation of mTORC1 helps resolve key discrepancies between rapid-acting antidepressants and local homeostatic mechanisms.

中文翻译：

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进行体内可塑性治疗抑郁症。

重度抑郁症（MDD）是一种复杂而异质的情绪障碍，因此很难开发出对所有MDD患者有效的通用药理疗法。通过偶然发现N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂作为有效的抗抑郁药，我们获得了关于如何在电路和分子水平上产生抗抑郁作用的重要见识。NMDAR拮抗剂起着快速作用的抗抑郁药的作用，从而使抑郁症状的缓解在单次注射后数小时内发生。NMDAR拮抗剂的作用方式似乎依赖于它们激活依赖蛋白质合成的体内平衡机制的能力，该机制可以恢复自上而下的兴奋性联系。最近的证据表明，NMDAR拮抗剂可通过形成新的突触来减轻抑郁症状，从而导致兴奋性驱动力增加。此事件需要雷帕霉素复合物1（mTORC1）的哺乳动物靶标，该靶标是调节突触蛋白合成的信号传导途径。本文中，我们回顾了批判性研究，这些研究揭示了NMDAR拮抗剂作为速效抗抑郁药的作用以及它们如何利用神经元或神经网络的稳态机制进行自我纠正。最近的研究特别表明，γ-氨基丁酸受体B（GABA 我们回顾了批判性研究，这些研究揭示了NMDAR拮抗剂作为速效抗抑郁药的作用以及它们如何利用神经元或神经网络的稳态机制进行自我纠正。最近的研究特别表明，γ-氨基丁酸受体B（GABA 我们回顾了批判性研究，这些研究揭示了NMDAR拮抗剂作为速效抗抑郁药的作用以及它们如何利用神经元或神经网络的稳态机制进行自我纠正。最近的研究特别表明，γ-氨基丁酸受体B（GABANMDAR拮抗剂的mTORC1依赖性翻译需要从抑制性到兴奋性的_B R）功能。最后，我们讨论了mTORC1的GABA _B R激活如何帮助解决速效抗抑郁药和局部稳态机制之间的关键差异。