The Role of FKBP5 in the Development of Post-Traumatic Stress Disorder
Introduction. Post-traumatic stress disorder (PTSD) is a psychiatric disorder characterized by abnormal, prolonged stress response to a trauma.1 Susceptibility to development of PTSD following exposure to trauma varies among individuals, suggesting that genetic and environmental factors modulate this stress response.1-5 FK506 Binding Protein 5 (FKBP5) is a major regulator of the stress response and decreases glucocorticoid (GC) sensitivity.3 FKBP5 has an association with PTSD susceptibility, though its mechanism and how it affects the pathophysiology of PTSD remain unclear.1,4 Studies suggest that elucidating its role in stress response and development of PTSD may spur developments in pharmacological therapies for PTSD.6,7 Methods. FKBP5-KO mice exposed to stress underwent behavioral testing (forced swim test, sucrose preference test, and novel object recognition test) and micro-RNA levels were quantified through qPCR.6 GFP-tagged rAAV or viral construct containing microRNA-690 (miR-690) was injected into the pre-limbic cortices of the medial prefrontal cortex through stereotaxic surgery.6 This was followed by sucrose preference test, forced swim test, novel object recognition test, and elevated plus maze test to identify changes in behavior.6 High throughput screen using LOPAC library in HeLa cells was used to identify compounds with the ability to rescue suppression of GR activity by FKBP51.7 In vitro flow cytometry protein interaction assay was used to validate disruption of the heterocomplex using benztropine, and Western blot on ex vivo brain slices used to verify results.7 Results. When FKBP5 was knocked, miR690 was overexpressed.6 Stressed, miR-690 overexpressing mice showed fewer behaviors associated with PTSD, including higher sucrose preference, lower immobility time, and increased interaction rate with a novel object, than control mice.6 This indicates that miR690 could prevent depressive behaviors and cognitive dysfunction following exposure to stress, and may be an epigenetic regulator of behavioral response following chronic stress.6 Benztropine mesylate was found to disrupt the FKBP51/GR/Hsp90 heterocomplex to selectively inhibit FKBP51 and therefore is a promising compound upon which to build FKBP5 inhibitors.7 Conclusion. Studies have begun to elucidate FKBP5’s mechanism and its connection to PTSD. PTSD is associated with high FKBP5 expression, which results in miR690 downregulation.6 miR690 and FKBP5 inhibitors therefore represent two promising avenues of pharmacological intervention in PTSD.7 Further research is needed to understand FKBP5’s effects on PTSD pathophysiology and to understand the role of various microRNAs affected by FKBP5.
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