Skip to content

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)

Read Full Text
Relevant Not relevant

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.

Comparable studies

Other preclinical and animal studies on ketamine for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Wistar-Kyoto (WKY) rats and Wistar control rats 2020 Preclinical study

Citations in the library

Cited by 5

Cites 31

and 26 more in the library

Related reading

Explore topics

Depression Ketamine Neuroplasticity Esketamine

By condition and practice

Ketamine for depression