Methionine mediates resilience to chronic social defeat stress by epigenetic regulation of NMDA receptor subunit expression

Interactive Effects of Methionine and Lead Intake on Cognitive Function among Chinese Adults

“…Prior evidence has indicated that methionine supplementation in lead-exposed rats led to improved cognitive function via the NMDAR NR1 mRNA and protein expression [ 26 , 27 ]. Bilen and colleagues also reported that methionine can decrease the expression of cortical NMDAR subunits through an epigenetic mechanism including increased histone methyltransferase and inhibit the levels of histone H3 lysine (K9) trimethylation, resulting in beneficial effects for attenuating stress in a murine model [ 14 ]. Despite methionine metabolism playing an important role in the regulation of the NMDAR pathway, there exist enormous gaps in the knowledge of their interaction in relation to cognition, which warrant further investigations.…”

“…On the other hand, methionine supplementation has been demonstrated to improve cognition in folate-deficient rat models [ 13 ]. Additionally, methionine treatment could promote resilience to chronic stress through an epigenetic mechanism (i.e., increasing histone methyltransferase and inhibiting the levels of histone H3 lysine (K9) trimethylation) [ 14 ]. Consistently, some evidence from investigations on human tissues has also shown that high methionine levels could protect the brain from damage [ 15 , 16 ].…”

Epigenetic mechanisms impacted by chronic stress across the rodent lifespan

“…Similar to findings following CSDS, adult male mice exposed to repeated restraint stress exhibit depressive-like behaviors and this was associated with a downregulation of G9a , and reduced H3K9me2 at the oxytocin and vasopressin promoters in the basolateral amygdala, effects that could be reversed by exercise ( Kim et al, 2016 ). CSDS also decreased Setdb1 /Setdb1, which is primarily responsible for tri-methylating lysine 9, specifically in adult male cortex of susceptible mice, and this was associated with a decrease in H3K9me3 ( Bilen et al, 2020 ). It was possible to promote resilience to the behavioural effects of CSDS and limit epigenetic changes by treating mice with a precursor to a methyl donor, methionine, during the defeat stress to restore methylation levels ( Bilen et al, 2020 ).…”

“…Additionally, mice resilient to CSDS have decreased expression of a gene encoding a DNA methyltransferase, Dnmt3a , in the PFC, and of a gene encoding the histone methyltransferase G9a in the hippocampus ( Mallei et al, 2019 ). The effect of CSDS on Dnmt3a in the cortex appears to be subregion specific, as a similar CSDS protocol induced an increase in Dnmt3a in whole cortex which was not dependent on the stress susceptibility or resilience of the animal ( Bilen et al, 2020 ).…”

“…It was possible to promote resilience to the behavioural effects of CSDS and limit epigenetic changes by treating mice with a precursor to a methyl donor, methionine, during the defeat stress to restore methylation levels ( Bilen et al, 2020 ). At this time, a number of studies discussing the involvement of histone methylation in the stress response, stress resilience and depression suggest that regulation of H3K9 methylation, and its associated gene repression, likely plays an important role in stress susceptibility and resilience albeit in a region-specific and cell-specific manner ( Bilen et al, 2020 ; Hamilton et al, 2018 ; Kim et al, 2016 ; Mallei et al, 2019 ; Wilkinson et al, 2009 ).…”