Figure 6.

Individual differences in naïve C57Bl6 mice in anxiety-related behavior reveal animals more sensitive to stress-induced down-regulation of hippocampal mGlu2 expression, a biomarker of depressive-like behavior and antidepressant response. The use of the light-dark test as a screening method (A) allows identification of clusters of animals with a different baseline anxiety profile (B), along with differences in mineralocorticoid receptor (MR) levels in hippocampus (C). The susceptible mice that are characterized by higher baseline MR levels show reduced hippocampal mGlu2 expression associated with exacerbation of anxious and of depressive-like behaviors after acute (D) and chronic stress, respectively. Conversely, individuals with lower baseline MR levels cope better with stress and show adaptation in mGlu2 receptor expression in hippocampus. The epigenetic allostasis model (E) points to the developmental origins of these individual differences, suggesting that as yet unknown epigenetic influences early in life may lead to alterations in MR hippocampal levels⁷¹. In (F) representative mechanisms of action of acetyl-L-carnitine (LAC): ours and other laboratories have shown that the decrease in mGlu2 receptors either following stress exposure or in a genetic animal model of depression is rapidly corrected by 3 days of intraperitoneal administration of the novel antidepressant candidate LAC via acetylation of either the H3K27 bound to Grm2 promoter, which codifies for mGlu2 receptors, or the NFkB/p65 sub-unit³².