Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis.
Neurobiology of disease September 1, 2024 Lijia Chang, Yan Wei, Youge Qu et al. 22 citations
In mice susceptible to chronic social defeat stress, removing the spleen reduces arketamine's antidepressant-like effects. RNA sequencing of the prefrontal cortex revealed that the oxidative phosphorylation (OXPHOS) pathway mediates this effect. Inhibiting OXPHOS with oligomycin A reversed the spleen removal's suppressive effect. Specific OXPHOS genes—COX11, UQCR11, and ATP5e—may be involved. Transforming growth factor β1 (TGF-β1) and COX11 appear to modulate the suppression; activating the TGF-β1 receptor with SRI-01138 alleviated it. Cutting the subdiaphragmatic vagus nerve also counteracted the inhibitory effect of splenectomy. These results suggest that arketamine's antidepressant-like effects involve the OXPHOS pathway and TGF-β1 in the prefrontal cortex, communicated through a spleen-brain axis via the vagus nerve.