Microglial BDNF modulates arketamine's antidepressant-like effects through cortico-accumbal pathways.
Lujuan He, Xuenan Wang, Shilin Luo, Nan Jiang, Yu Yan, Min Xie, Yueyue Chen, Chun Yang, Wei Yao, Kenji Hashimoto, Ji-Chun Zhang
Science Advances July 11, 2025 DOI: 10.1126/sciadv.adv5986 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Mice exposed to chronic social defeat stress (CSDS) |
| Intervention | Arketamine |
| Topics | Depression Ketamine Neuroplasticity |
| Keywords | Microglia Brain immune cells Glial cells Brain cells Antidepressant Mood elevator Psychiatric medication Psychotropic drug Neurobiology Brain science Brain mechanism Bdnf Mental health Chronic stress Psychiatric health Emotional well-being |
| Citations | 8 |
| Key points | Microglia-derived BDNF, driven by CREB and MeCP2 activation, enhances excitatory synaptic transmission in the infralimbic mPFC and activates NAc-projecting mPFC neurons, mediating arketamine's antidepressant-like effects in CSDS-susceptible mice. |
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.