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Microglial BDNF modulates arketamine's antidepressant-like effects through cortico-accumbal pathways
Lujuan He1,2, Xuenan Wang2, Shilin Luo3
1Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China.
Science Advances
|July 9, 2025
Summary
Arketamine, a ketamine enantiomer, demonstrates potent antidepressant effects by activating CREB and MeCP2, leading to increased BDNF. Microglia-derived BDNF in the mPFC is crucial for these therapeutic actions.
Area of Science:
- Neuroscience
- Molecular Psychiatry
- Pharmacology
Background:
- Arketamine, the (R)-enantiomer of ketamine, exhibits superior antidepressant-like effects in preclinical models compared to esketamine.
- The precise molecular mechanisms underlying arketamine's rapid and sustained antidepressant actions remain largely undetermined.
Purpose of the Study:
- To elucidate the neurobiological pathways through which arketamine exerts its antidepressant-like effects.
- To investigate the role of specific signaling molecules and neuronal circuits in mediating arketamine's efficacy.
Main Methods:
- Utilized the chronic social defeat stress (CSDS) mouse model to simulate depression-like behaviors.
- Examined the activation of cAMP response element-binding protein (CREB) and methyl-CpG-binding protein 2 (MeCP2) following arketamine administration.
- Assessed the contribution of brain-derived neurotrophic factor (BDNF) released from microglia.
Main Results:
- Arketamine administration increased the phosphorylation of CREB at S133 and MeCP2 at S421, driving BDNF transcription.
- Microglia-derived BDNF was found to enhance excitatory synaptic transmission in the infralimbic (IL) region of the medial prefrontal cortex (mPFC).
- Microglia-derived BDNF modulated the activity of mPFC (IL) neurons projecting to the nucleus accumbens (NAc) shell.
Conclusions:
- Activation of CREB and MeCP2 by arketamine promotes BDNF transcription, contributing to its antidepressant-like effects.
- Microglia-derived BDNF plays a critical role in mediating arketamine's antidepressant actions by enhancing synaptic function in the mPFC.
- Arketamine's therapeutic effects involve the modulation of mPFC-NAc circuitry via microglial BDNF signaling.
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