He Lujuan, Wang Xuenan, Luo Shilin, Jiang Nan, Yan Yu, Xie Min, Chen Yueyue, Yang Chun, Yao Wei, Hashimoto Kenji, Zhang Ji-Chun
Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China.
Institute of Brain Science and Brain-inspired Research, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China.
Sci Adv. 2025 Jul 11;11(28):eadv5986. doi: 10.1126/sciadv.adv5986. Epub 2025 Jul 9.
Arketamine, the ()-enantiomer of ()-ketamine, shows even greater rapid and sustained antidepressant-like effects in rodent models compared to esketamine, yet the underlying mechanisms remain unclear. In this study, we used the chronic social defeat stress (CSDS) model to investigate how arketamine exerts its antidepressant-like effects. We found that activating cAMP response element-binding protein (CREB) at S133 and methyl-CpG-binding protein 2 (MeCP2) at S421 drives the transcription of brain-derived neurotrophic factor (BDNF), contributing to arketamine's antidepressant-like effects. Furthermore, microglia-derived BDNF enhances excitatory synaptic transmission in the infralimbic (IL) region of the medial prefrontal cortex (mPFC), mediating the antidepressant-like effects of arketamine in CSDS-susceptible mice. Last, microglia-derived BDNF can activate mPFC (IL) neurons projecting to the nucleus accumbens (NAc) shell, contributing to arketamine's antidepressant-like effects. These findings highlight the essential role of microglial BDNF in modulating NAc-projecting mPFC neurons, which contribute to the antidepressant-like effects of arketamine.
阿氯胺酮是氯胺酮的（）-对映体，与艾氯胺酮相比，在啮齿动物模型中显示出更强的快速和持续的抗抑郁样作用，但其潜在机制仍不清楚。在本研究中，我们使用慢性社会挫败应激（CSDS）模型来研究阿氯胺酮如何发挥其抗抑郁样作用。我们发现，在S133位点激活环磷酸腺苷反应元件结合蛋白（CREB）和在S421位点激活甲基化CpG结合蛋白2（MeCP2）可驱动脑源性神经营养因子（BDNF）的转录，从而产生阿氯胺酮的抗抑郁样作用。此外，小胶质细胞源性BDNF增强内侧前额叶皮质（mPFC）腹内侧（IL）区域的兴奋性突触传递，介导阿氯胺酮对CSDS敏感小鼠的抗抑郁样作用。最后，小胶质细胞源性BDNF可激活投射到伏隔核（NAc）壳的mPFC（IL）神经元，从而产生阿氯胺酮的抗抑郁样作用。这些发现突出了小胶质细胞BDNF在调节投射到NAc的mPFC神经元中的重要作用，这有助于阿氯胺酮的抗抑郁样作用。
