PET imaging evidence of HDAC6 suppression in the amygdala across species in PTSD

Abstract

Histone deacetylases (HDACs), typically known for regulating gene expression, also play a major role in protein regulation outside of histone modification. Emerging evidence suggests the HDACs may be novel pharmacologic targets in complex disorders such as posttraumatic stress disorder (PTSD). Histone deacetylase 6 (HDAC6) regulates microtubule function and plays a role in stress-related cortisol signaling in serotonergic regions of the brain by maintaining the nuclear translocation of glucocorticoid receptors. Here, we report results of a translational positron emission tomography brain imaging study using a novel HDAC6-selective radiotracer, [18F]Bavarostat. In humans, we demonstrate significantly lower availability of HDAC6 in the amygdala of individuals with PTSD compared to non-trauma exposed controls. These proof-of-concept human findings are supported by rodent findings of reduced HDAC6 availability both in case-control groups and within-subject longitudinal analysis using a single prolonged stress model. Together, our translational findings demonstrate a potential role for HDAC6 in the pathophysiology of PTSD.