Stress-induced mechanisms in mental illness: A role for glucocorticoid signalling

Abstract

Stress represents the main environmental risk factor for mental illness. Exposure to stressful events, particularly early in life, has been associated with increased incidence and susceptibility of major depressive disorders as well as of other psychiatric illnesses. Among the key players in these events are glucocorticoid receptors. Dysfunctional glucocorticoid signalling may indeed contribute to psychopathology through a number of mechanisms that regulate the response to acute or chronic stress and that affect the function of genes and systems known to be relevant for mood disorders. Indeed, exposure to chronic stress early in life as well as in adulthood has been shown to reduce the expression of glucocorticoid receptors (GR), also through epigenetic mechanisms, and to up-regulate the expression of the co-chaperone gene FKBP5, which restrains GR activity by limiting the translocation of the receptor complex to the nucleus. Another mechanism that contributes to changes in GR responsiveness is the state of receptor phosphorylation that controls activation, subcellular localization as well as its transcriptional activity. Moreover, GR phosphorylation may represent an important mechanism for the cross talk between neurotrophic signalling and GR-dependent transcription, bridging two important players for mood disorders. One gene that lies downstream from GR and may contribute to stress-related changes is serum glucocorticoid kinase-1 (SGK1). We have demonstrated that the expression of SGK1 is significantly increased after exposure to chronic stress in rodents as well as in the blood of drug-free depressed patients. We have also shown that SGK1 up-regulation may ultimately reduce hippocampal neurogenesis and contribute to the structural abnormalities that have been reported to occur in depressed patients. In summary, GR signalling may represent a point of convergence as well as of divergence for defects associated with pathologic conditions characterized by heightened vulnerability to stress. The characterization of these abnormalities is crucial to identify novel targets for therapeutic intervention that may counteract more effectively stress-induced neurobiological abnormalities.

Keywords: BDNF; DNA methylation; FKBP5; Mood disorders; SGK1.