Rapid Antidepressant Effect of Hydrogen Sulfide: Evidence for Activation of mTORC1-TrkB-AMPA Receptor Pathways.

AIMS: We asked whether hydrogen sulfide (H2 S), as the third gaseous mediator, provided fast antidepressant effect on major depressive disorders and underlying mechanisms.

RESULTS: The decreased level of H2 S was detected in the hippocampus of chronic unpredictable mild stress (CUMS)-treated rats. Acute administration of H2 S either by H2 S inhalation or by the donor NaHS produced a rapid antidepressant-like behavioral effect. Further investigation demonstrated that this effect of H2 S was mediated by reversing the CUMS-induced decrease in dendritic spine density and required the activation of mammalian target of rapamycin (mTOR)C1 and neurotrophic TrkB receptors, which proceeded to increase synaptic protein expression, including postsynaptic density protein 95, synaptophysin, and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor GluR1/2 subunit.

INNOVATION: This study provides the first direct evidence for detecting the decreased H2 S in hippocampus of CUMS rats and the biological significance of H2 S in treating major depression.

CONCLUSION: Our data demonstrate that H2 S activates mTORC1 signaling cascades and thereby produces fast-onset antidepressant effect. The study provides a profound insight into H2 S or its donors as potent preventive and therapeutic agents for intervention of depression. Antioxid. Redox Signal. 27, 472-488.