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 via PubMed
Summary
AI-generated from the abstractArketamine, the (R)-enantiomer of ketamine, produces faster and longer-lasting antidepressant-like effects than esketamine in mice subjected to chronic social defeat stress. Activating the proteins CREB and MeCP2 drives the production of brain-derived neurotrophic factor (BDNF) in microglia, the brain's immune cells. This microglia-derived BDNF strengthens excitatory synaptic transmission in the infralimbic region of the medial prefrontal cortex (mPFC). It also activates mPFC neurons that project to the nucleus accumbens (NAc) shell, a brain area involved in reward and mood. These mechanisms together underlie arketamine's antidepressant-like effects, highlighting the essential role of microglial BDNF in modulating this neural pathway.
Study at a glance
| 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 |
| Citations | 8 |
| Key finding | 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.