Department of Pharmacology and the Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA.
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Cell Rep. 2021 Nov 2;37(5):109918. doi: 10.1016/j.celrep.2021.109918.
Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid antidepressant action of ketamine. Here, we combine genetic, electrophysiological, and pharmacological strategies to investigate the role of eEF2K in synaptic function and find that acute, but not chronic, inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus. Retinoic acid (RA) signaling also elicits a similar form of rapid synaptic scaling in the hippocampus, which we observe is independent of eEF2K functioni. The RA signaling pathway is not required for ketamine-mediated antidepressant action; however, direct activation of the retinoic acid receptor α (RARα) evokes rapid antidepressant action resembling ketamine. Our findings show that ketamine and RARα activation independently elicit a similar form of multiplicative synaptic scaling that is causal for rapid antidepressant action.
氯胺酮是一种非竞争性谷氨酸能 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，具有快速抗抑郁作用。临床前研究确定真核延伸因子 2 激酶（eEF2K）信号对于氯胺酮的快速抗抑郁作用至关重要。在这里，我们结合遗传、电生理和药理学策略来研究 eEF2K 在突触功能中的作用，发现急性而非慢性抑制 eEF2K 活性会在海马体中诱导快速的突触缩放。视黄酸（RA）信号也会在海马体中引发类似的快速突触缩放，我们观察到这与 eEF2K 功能无关。RA 信号通路不是氯胺酮介导的抗抑郁作用所必需的；然而，直接激活视黄酸受体 α（RARα）会引发类似于氯胺酮的快速抗抑郁作用。我们的研究结果表明，氯胺酮和 RARα 激活独立地引发类似的乘法性突触缩放，这是快速抗抑郁作用的因果关系。
