Arthi Tarugu

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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