Kappa opioid receptor induces epigenetic silencing of brain derived neurotropic factor via HDAC5 in treatment-resistant depression

Abstract

AbstractTreatment-resistant depression (TRD) occurs in almost 50% of depressed patients. Although modulation of brain-derived neurotrophic factor (BDNF) expression in major depression and antidepressant treatment is well established, the mechanisms of BDNF regulation in TRD are not clear. Previously, we have shown that chronic kappa opioid receptor (KOR) stimulation leads to TRD-like phenotype in mice, and modulation of BDNF expression in the prefrontal cortex appears to be one of the molecular determinants of the antidepressant response. Considering the role of various epigenetic pathways in BDNF expression, in this study we investigated the role of histone deacetylase (HDACs) in KOR induced BDNF downregulation in mice. First, we showed that sustained KOR activation by its agonist, U50488 resulted in selective and specific downregulation of acetylation at the 9th lysine residue of the histone H3 protein (H3K9ac) and upregulation of HDAC5 in the prefrontal cortex (PFC). However, no change was observed in H3K9ac levels in the PFC of chronic unpredictable stress-exposed mice. Further, KOR activation led to specific downregulation ofBdnf II,andIVtranscripts in the PFC and primary cortical neurons. Using chromatin immune precipitation assay, we detected decreased H3K9ac levels, while increased HDAC5 binding atBdnf IIandIVpromoters, which were blocked by a selective KOR antagonist,norbinaltorphimine. Further mechanistic studies using HDAC5 selective inhibitor LMK235 in primary cortical neurons, we confirmed the essential role of HDAC5 in KOR-mediated reduction ofBdnfexpression in PFC. These results suggest that KOR engages multiple pathways in TRD, and may be targeted for the development of new therapeutics for treatment-resistant depression.