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  3. Microglial BDNF modulates arketamine's antidepressant-like effects through cortico-accumbal pathways

Microglial BDNF modulates arketamine's antidepressant-like effects through cortico-accumbal pathways

  • Sci Adv. 2025 Jul 11;11(28):eadv5986. doi: 10.1126/sciadv.adv5986.
Lujuan He 1 2,  Xuenan Wang 2,  Shilin Luo 3,  Nan Jiang 2,  Yu Yan 1,  Min Xie 1,  Yueyue Chen 4,  Chun Yang 5,  Wei Yao 4,  Kenji Hashimoto 6,  Ji-Chun Zhang 1 2
Affiliations

Affiliations

  • 1 Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China.
  • 2 Institute of Brain Science and Brain-inspired Research, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China.
  • 3 Department of Neurology, Xiangya Hospital, National Clinical Research Center for Geriatric Disorders, and Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 4 Guangzhou Key Laboratory of Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China.
  • 5 Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 6 Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
PMID: 40632846 DOI: 10.1126/sciadv.adv5986
Abstract

Arketamine, the (R)-enantiomer of (R,S)-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.

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