Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as Key Factor for Depression

Abstract Background Depression is frequently associated with chronic pain or chronic stress. Among cortical areas, the anterior cingulate cortex (ACC, areas 24a/24b), appears important for mood disorders and constitutes a neuroanatomical substrate for investigating the underlying molecular mechanisms. Present work aimed at identifying ACC molecular factors subserving depression. Methods Anxiodepressive-like behaviors in C57BL/6J male mice were induced by neuropathic pain, unpredictable chronic mild stress (UCMS) and optogenetic ACC stimulation, and evaluated using novelty suppressed feeding, splash and forced swimming tests. ACC molecular changes in chronic pain-induced depression were uncovered through whole-genome expression analysis. Further mechanistic insights were provided by chromatin immunoprecipitation, Western blot and immunostaining. The causal link between molecular changes and depression was studied using knock-out, pharmacological antagonism and local viral-mediated gene knock-down. Results Under chronic pain-induced depression, gene expression changes in the ACC highlighted the overexpression of a regulator of the mitogen-activated protein kinase (MAPK) pathway, the MAPK Phosphatase-1 (MKP-1). This upregulation is associated with the presence of transcriptionally active chromatin marks (acetylation) at its proximal promoter region, as well as an increased cAMP response element (CRE)-mediated transcriptional activity, and phosphorylation of CREB and ATF. MKP-1 overexpression is also observed with the UCMS and repeated ACC optogenetic stimulation, and is reversed by fluoxetine. A knock-out, an antagonist or a local silencing of MKP-1 attenuates depressive-like behaviors, pointing to an important role of this phosphatase in depression. Conclusions These data point to ACC MKP-1 as a key factor in the pathophysiology of depression, and a potential target for treatment development.