Differences in FKBP51 regulation following chronic social defeat stress correlate with individual stress sensitivity: influence of paroxetine treatment.

Various clinical studies have identified FK506-binding protein 51 (FKBP51) as a target gene involved in the development of psychiatric disorders such as depression. Furthermore, FKBP51 has been shown to affect glucocorticoid receptor signaling by sensitivity modulation and it is implicated in stress reactivity as well as in molecular mechanisms of stress vulnerability and resilience. We investigated the physiological, behavioral, and neuroendocrine parameters in an established chronic stress model both directly after stress and after a recovery period of 3 weeks and also studied the efficacy of paroxetine in this model. We then examined FKBP51 mRNA levels in the dorsal and ventral part of the hippocampus and correlated the expression to behavioral and endocrine parameters. We show robust chronic stress effects in physiological, behavioral, and neuroendocrine parameters, which were only slightly affected by paroxetine treatment. On the contrary, paroxetine led to a disruption of the neuroendocrine system. FKBP51 expression was significantly increased directly after the stress period and correlated with behavioral and neuroendocrine parameters. Taken together, we were able to further elucidate the role of FKBP51 in the mechanisms of stress resilience and vulnerability, especially with respect to behavioral and neuroendocrine parameters. These findings strongly support the concept of FKBP51 as a marker for glucocorticoid receptor sensitivity and its involvement in the development of psychiatric disorders.

Fkbp52 heterozygosity alters behavioral, endocrine and neurogenetic parameters under basal and chronic stress conditions in mice.

Aversive life events represent one of the main risk factors for the development of many psychiatric diseases, but the interplay between environmental factors and genetic predispositions is still poorly understood. One major finding in many depressed patients is an impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The negative feedback loop of the HPA axis is mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The co-chaperones FK506-binding protein 51 (FKBP51) and FK506-binding protein 52 (FKBP52) are components of the heat shock protein 90-receptor-heterocomplex and are functionally divergent regulators of both receptors. Here, we characterized heterozygous Fkbp52 knockout (Fkbp52(+/-)) mice under basal or chronic social defeat stress (CSDS) conditions with regard to physiological, neuroendocrine, behavioral and mRNA expression alterations. Fkbp52(+/-) mice displayed symptoms of increased stress sensitivity in a subset of behavioral and neuroendocrine parameters. These included increased anxiety-related behavior in the elevated plus-maze and an enhanced neuroendocrine response to a forced swim test (FST), possibly mediated by reduced GR sensitivity. At the same time, Fkbp52(+/-) mice also demonstrated signs of stress resilience in other behavioral and neuroendocrine aspects, such as reduced basal corticosterone levels and more active stress-coping behavior in the FST following CSDS. These contrasting results are in line with previous reports showing that FKBP52 is not involved in all branches of GR signaling, but rather acts in a gene-specific manner to regulate GR transcriptional activation.