Details

Autor(en) / Beteiligte

• Zhu, Li‐Juan
• Ni, Huan‐Yu
• Chen, Rong
• Chang, Lei
• Shi, Hu‐Jiang
• Qiu, Dan
• Zhang, Zhan
• Wu, Dan‐Lian
• Jiang, Zhao‐Chun
• Xin, Hong‐Liang
• Zhou, Qi‐Gang
• Zhu, Dong‐Ya

Titel

Hippocampal nuclear factor kappa B accounts for stress‐induced anxiety behaviors via enhancing neuronal nitric oxide synthase (nNOS)‐carboxy‐terminal PDZ ligand of nNOS‐Dexras1 coupling

Ist Teil von

• Journal of neurochemistry, 2018-09, Vol.146 (5), p.598-612

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Anxiety disorders are associated with a high social burden worldwide. Recently, increasing evidence suggests that nuclear factor kappa B (NF‐κB) has significant implications for psychiatric diseases, including anxiety and depressive disorders. However, the molecular mechanisms underlying the role of NF‐κB in stress‐induced anxiety behaviors are poorly understood. In this study, we show that chronic mild stress (CMS) and glucocorticoids dramatically increased the expression of NF‐κB subunits p50 and p65, phosphorylation and acetylation of p65, and the level of nuclear p65 in vivo and in vitro, implicating activation of NF‐κB signaling in chronic stress‐induced pathological processes. Using the novelty‐suppressed feeding (NSF) and elevated‐plus maze (EPM) tests, we found that treatment with pyrrolidine dithiocarbamate (PDTC; intra‐hippocampal infusion), an inhibitor of NF‐κB, rescued the CMS‐ or glucocorticoid‐induced anxiogenic behaviors in mice. Microinjection of PDTC into the hippocampus reversed CMS‐induced up‐regulation of neuronal nitric oxide synthase (nNOS), carboxy‐terminal PDZ ligand of nNOS (CAPON), and dexamethasone‐induced ras protein 1 (Dexras1) and dendritic spine loss of dentate gyrus (DG) granule cells. Moreover, over‐expression of CAPON by infusing LV‐CAPON‐L‐GFP into the hippocampus induced nNOS‐Dexras1 interaction and anxiety‐like behaviors, and inhibition of NF‐κB by PDTC reduced the LV‐CAPON‐L‐GFP‐induced increases in nNOS‐Dexras1 complex and anxiogenic‐like effects in mice. These findings indicate that hippocampal NF‐κB mediates anxiogenic behaviors, probably via regulating the association of nNOS‐CAPON‐Dexras1, and uncover a novel approach to the treatment of anxiety disorders. The molecular mechanisms underlying anxiety behaviors are poorly understood. Here, we propose a model of a signaling cascade whereby hippocampal nuclear factor kappa B (NF‐κB) contributes to chronic stress‐induced anxiety behaviors. Activation of NF‐κB signaling by chronic stress‐stimulated glucocorticoid overproduction leads to up‐regulation of neuronal nitric oxide synthase (nNOS), carboxy‐terminal PDZ ligand of nNOS (CAPON), and dexamethasone‐induced ras protein 1 (Dexras1) expression and nNOS‐CAPON‐Dexras1 association, thus inducing anxiety‐related behaviors. Our findings suggest a new target for the intervention of anxiety‐related disorders.