Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis.
Lijia Chang, Yan Wei, Youge Qu, Mingming Zhao, Xiangyu Zhou, Yang Long, Kenji Hashimoto
Neurobiology of Disease September 1, 2024 DOI: 10.1016/j.nbd.2024.106573 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study in a mouse model Peer reviewed |
|---|---|
| Population | CSDS-susceptible mice |
| Interventions | Arketamine splenectomy oligomycin A SRI-01138 subdiaphragmatic vagotomy |
| Topics | Ketamine |
| Keywords | Oxidative phosphorylation Spleen-brain axis Vagus nerve Depression treatment Neuroscience research Metabolic pathways Antidepressant mechanisms Brain-body connection |
| Citations | 22 |
| Key findings | The spleen-brain axis, mediated by the vagus nerve and involving the OXPHOS pathway and TGF-β1 in the prefrontal cortex, contributes to arketamine's antidepressant-like effects in mice. |
Abstract
Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the oxidative phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-β1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-β1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-β1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve.