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DOI: 10.1055/s-0029-1240127
The involvement of FKBP5 in the behavioural and neuroendocrine effects of acute and chronic stress
Chronic stress is a major risk factor for depression and an impaired negative feedback of the hypothalamic-pituitary-adrenal axis has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the hypothalamic-pituitary-adrenal axis, are mediated via two receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Genetic alterations in the cochaperone FKBP5, which interacts with both receptor types, predispose individuals to be more sensitive to chronic stress and are associated with an increased recurrence of depressive episodes. Since, moreover, FKBP5 plays a key role in regulating GR function, we postulate that it is causally involved in the development of stress-related disorders. We investigated the consequences of three weeks of chronic social defeat stress (CSDS) in FKBP5 knockout mice and wild type controls. CSDS resulted in a number of behavioural, physiological and neuroendocrine alterations in wild type mice, including augmented adrenal weight, elevated basal corticosterone levels and increased anxiety-related behaviour. Mice lacking FKBP5 showed a diminished physiological and neuroendocrine response to CSDS, with no alteration in anxiety. In conclusion, our data suggest an enhancement of the negative glucocorticoid feedback within the hypothalamic-pituitary-adrenal axis in FKBP5 knockout mice, possibly due to a more sensitive GR.