A synaptic role of FKBP5 in stress-related neuropsychiatric disorders

The development of psychiatric disorders, such as depression, post-traumatic stress-disorder, and bipolar disorder has been shown to be associated with alterations in neuronal structure and function, particularly in the cerebral cortex. While recent large scale clinical genomics studies have identified genetic risk factors for psychiatric disorders, the functional analysis of these risk genes and their encoded proteins is the next major challenge. Among these, FKBP5, encoding FK506 binding protein 5, is a prominent genetic risk factor for stress-related mood and anxiety disorders, including depression and post-traumatic stress-disorder. However, the mechanisms by which FKBP5 contributes to disease pathogenesis are not well understood. While a role for FKBP5 as a glucocorticoid receptor co-chaperone have been postulated, additional mechanisms have not been investigated in the brain. We hypothesized that FKBP5 may also function at synapses, sites relevant for the pathogenesis of psychiatric disorders. By utilizing an in vitro model of stress and primary rodent cortical cultures we have found independent effects of stress and FKBP5 on neuronal morphology. Furthermore, our super-resolution microscopy and live cell imaging techniques have revealed a unique synaptic role of FKBP5. Further studies investigating the molecular pathways involved in FKBP5-mediated synaptic processes can provide insight into disease pathogenesis and lead to novel therapeutic strategies.