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

Abstract

Rationale: Previous studies suggested that methionine (Met) levels are decreased in depressed patients. However, whether the decrease in this amino acid is important for phenotypic behaviors associated with depression has not been deciphered.

Objective: The response of individuals to chronic stress is variable, with some individuals developing depression and others becoming resilient to stress. In this study, our objective was to examine the effect of Met on susceptibility to stress.

Methods: Male C57BL/6J mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day 11, the behavior of mice was assessed using social interaction and open-field tests. Mice received Met 4 h before each defeat session. Epigenetic targets were assessed either through real-rime RTPCR or through Western Blots.

Results: Met did not modulate anxiety-like behaviors, but rather promoted resilience to chronic stress, rescued social avoidance behaviors and reversed the increase in the cortical expression levels of N-methyl-D-aspartate receptor (NMDAR) subunits. Activating NMDAR activity abolished the ability of Met to promote resilience to stress and to rescue social avoidance behavior, whereas inhibiting NMDAR did not show any synergistic or additive protective effects. Indeed, Met increased the cortical levels of the histone methyltransferase SETDB1, and in turn, the levels of the repressive histone H3 lysine (K9) trimethylation (me3).

Conclusions: Our data indicate that Met rescues susceptibility to stress by inactivating cortical NMDAR activity through an epigenetic mechanism involving histone methylation.

Keywords: Chronic social defeat stress; Depression; Grin1; Grin2; Histone H3K9 trimethylation; Methionine; SETDB1.