S-adenosyl-L-methionine modulates hippocampal DNA methylation, exerting fast and long-lasting anti-stress effects independent of alterations in TrkB-mTOR expression

Emerging evidence suggests that targeting DNA methylation, a key epigenetic mechanism, may represent a promising therapeutic approach for the treatment of stress-related disorders, including depression. Preclinical studies indicate that the inhibition of DNA methylation induces rapid and sustained antidepressant-like effects through the increased BDNF-TrkB-mTOR signaling in the prefrontal cortex, a brain region associated to the neurobiology of depression and neuroplasticity. S-adenosyl-l-methionine (SAMe), a methyl donor, has been shown to reverse depressive-like behaviors by modulating DNA methylation. However, the molecular mechanisms underlying the SAMe antidepressant effects are not yet fully understood. Therefore, this study evaluated whether SAMe induces rapid and long-lasting behavioral effects by modulating DNA methylation and mTOR-TrkB expression in mice. For this purpose, male Swiss mice received intraperitoneal (i.p.) injections of SAMe (25, 50, and 100 mg/kg) or vehicle (10 mL/kg), 30 minutes, 7 days, or 14 days prior to the forced swimming test (FST) or tail suspension test (TST), two predictive tests of antidepressant action. Global DNA methylation and mTOR-TrkB levels were measured in the hippocampus and prefrontal cortex. SAMe (50 mg/kg) induced a rapid and sustained decrease in immobility time in both the FST and TST, and prevented the stress-induced effects in hippocampal DNA methylation without changing the analyzed protein expression. These findings suggest that the rapid and sustained anti-stress effects observed in mice, resulting from the modulation of hippocampal DNA methylation due to acute SAMe treatment, are not related with TrkB-mTOR signaling.