Mood disorders affect nearly a quarter of the world's population. Therefore, understanding the molecular mechanisms underlying these conditions is of great importance. FK-506 binding protein 5 ( FKBP5 ) encodes the FKBP51 protein, a heat shock protein 90 kDa (Hsp90) co-chaperone, and is a risk factor for several affective disorders. FKBP51, in coordination with Hsp90, regulates glucocorticoid receptor (GR) activity via a short negative feedback loop. This signalling pathway rapidly restores homeostasis in the hypothalamic–pituitary–adrenal (HPA) axis following stress. Expression of FKBP5 increases with age through reduced DNA methylation. High levels of FKBP51 are linked to GR resistance and reduced stress coping behaviour. Moreover, common allelic variants in the FKBP5 gene are associated with increased risk of developing affective disorders like anxiety, depression and post-traumatic stress disorder (PTSD). This review highlights the current understanding of the Hsp90 co-chaperone, FKBP5, in disease from both human and animal studies. In addition, FKBP5 genetic implications in the clinic involving life stress exposure, gender differences and treatment outcomes are discussed. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

Increased expression of the FK506-binding protein 5 (FKBP5) gene has been associated with a number of diseases, but most prominently in connection to psychiatric illnesses. Many of these psychiatric disorders present with dementia and other cognitive deficits, but a direct connection between these issues and alterations inFKBP5remains unclear. We generated a novel transgenic mouse to selectively overexpressFKBP5,which encodes the FKBP51 protein, in the corticolimbic system, which had no overt effects on gross body weight, motor ability, or general anxiety. Instead, we found that overexpression of FKBP51 impaired long-term depression (LTD) as well as spatial reversal learning and memory, suggesting a role in glutamate receptor regulation. Indeed, FKBP51 altered the association of heat-shock protein 90 (Hsp90) with AMPA receptors, which was accompanied by an accelerated rate of AMPA recycling. In this way, the chaperone system is critical in triage decisions for AMPA receptor trafficking. Imbalance in the chaperone system may manifest in impairments in both inhibitory learning and cognitive function. These findings uncover an unexpected and essential mechanism for learning and memory that is controlled by the psychiatric risk factorFKBP5.

Early life stress (ELS) adversely affects the brain and is commonly associated with the etiology of mental health disorders, like depression. In addition to the mood-related symptoms, patients with depression show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased peripheral inflammation, and structural brain alterations. Although the underlying causes are unknown, polymorphisms in the FK506-binding protein 5 (FKBP5) gene, a regulator of glucocorticoid receptor (GR) activity, interact with childhood adversities to increase vulnerability to depressive disorders. We hypothesized that high FKBP5 protein levels combined with early life stress (ELS) would alter the HPA axis and brain, promoting depressive-like behaviors. To test this, we exposed males and females of a mouse model overexpressing FKBP5 in the brain (rTgFKBP5 mice), or littermate controls, to maternal separation for 14 days after birth. Then, we evaluated neuroendocrine, behavioral, and brain changes in young adult and aged mice. We observed lower basal corticosterone (CORT) levels in rTgFKBP5 mice, which was exacerbated in females. Aged, but not young, rTgFKBP5 mice showed increased depressive-like behaviors. Moreover, FKBP5 overexpression reduced hippocampal neuron density in aged mice, while promoting markers of microglia expression, but these effects were reversed by ELS. Together, these results demonstrate that high FKBP5 affects basal CORT levels, depressive-like symptoms, and numbers of neurons and microglia in the hippocampus in an age-dependent manner.

Fear extinction correlates with increased infralimbic (IL) neuronal excitability. Since small conductance Ca2+-dependent K+ (SK) channels modulate neuronal excitability and certain types of learning and memory, pharmacological modulation of SK channels could be used to regulate IL excitability and fear extinction. To test this, we first determined the effect of blocking SK channels with apamin on the intrinsic excitability of IL pyramidal neurons in brain slices. In whole-cell patch-clamp recordings, apamin increased the number of spikes evoked by a depolarizing current pulse, increased the firing frequency, and reduced the fast hyperpolarizing potential (fAHP) indicating that blockade of SK channels could be used to enhance the intrinsic excitability of IL neurons. Next, we assessed whether SK channels in IL regulate extinction of conditioned fear by infusing apamin into IL of fear conditioned rats prior to extinction training. Apamin infusion did not affect conditioned freezing at the beginning of the extinction session or within-session extinction. However, the following day, apamin-infused rats showed significantly less conditioned freezing. To further examine the importance of SK channels in IL in fear extinction, we assessed the effect of the SK channel activator DCEBIO on IL neuronal excitability and fear extinction. Activation of SK channels with DCEBIO decreased the number of evoked spikes, reduced the firing frequency, and enhanced the fAHP of IL neurons. Infusion of DCEBIO into IL prior to fear extinction impaired recall of fear extinction without affecting acquisition of extinction. Taken together, these findings suggest that SK channels are involved in regulating IL excitability and extinction-induced plasticity. Therefore, SK channels are a potential target for the development of new pharmacological treatments to facilitate extinction in patients suffering from anxiety disorders.

The factors influencing resiliency to the development of post-traumatic stress disorder (PTSD) remain to be elucidated. Clinical studies associate PTSD with polymorphisms of the FK506 binding protein 5 (FKBP5). However, it is unclear whether changes in FKBP5 expression alone could produce resiliency or susceptibility to PTSD-like symptoms. In this study, we used rats as an animal model to examine whether FKBP5 in the infralimbic (IL) or prelimbic (PL) medial prefrontal cortex regulates fear conditioning or extinction. First, we examined FKBP5 expression in IL and PL during fear conditioning or extinction. In contrast to the stable expression of FKBP5 seen in PL, FKBP5 expression in IL increased after fear conditioning and remained elevated even after extinction suggesting that IL FKBP5 levels may modulate fear conditioning or extinction. Consistent with this possibility, reducing basal FKBP5 expression via local infusion of FKBP5–shRNA into IL reduced fear conditioning. Furthermore, reducing IL FKBP5, after consolidation of the fear memory, enhanced extinction memory indicating that IL FKBP5 opposed formation of the extinction memory. Our findings demonstrate that lowering FKBP5 expression in IL is sufficient to both reduce fear acquisition and enhance extinction, and suggest that lower expression of FKBP5 in the ventral medial prefrontal cortex could contribute to resiliency to PTSD.