Methionine mediates resilience to chronic social defeat by modulating NMDA receptor expression in the cortex. (c2018)

Abstract

Nowadays, Major Depressive Disorder (MDD) has become a leading cause of disability in the world. Most patients suffering from depression are treated with serotonin reuptake inhibitors, but resistance has started emerging. Therefore, alternative treatments should be considered. Recent studies have shown that the brains of individuals affected with neuropsychiatric disorders have disrupted methylation patterns. Since methionine is the precursor of S-adenosylmethionine (SAM), a cofactor for most methyltransferases, the aim of the study was to examine the effect of methionine supplementation on chronic social defeat (CSD), the animal model of depression. Male C57BL/6 mice were subjected to CSD for 10 consecutive days, followed by behavioral testing to assess anxiety and depression-like symptoms. Animals subjected to CSD and treated with 1.55mg/Kg of methionine through intraperitoneal injections, showed a rescue in the social avoidance behavior. Molecular analysis of the cortices of these animals revealed that methionine treatment restored the expression levels of NMDA receptor subunits, Grin 1, Grin 2a and Grin 2b to baseline when compared to the increased levels observed in defeated animals treated with saline only. This increase was accompanied by a reduction in the protein levels of the histone methyltransferase known to modulate NMDA receptor expression, SetDB1 in defeated animals, while methionine injections returned SetDB1 levels to baseline. These findings suggest that methionine supplementation could serve as an antidepressant due to its role in modifying the histone methylation patterns and possibly regulating the NMDA gene expression.