BDNF-Related Imbalance of Copine 6 and Synaptic Plasticity Markers Couples With Depression-Like Behavior and Immune Activation in CUMS Rats.

Chen Tao,Le-le Wang,Yin-xiu Han,Chong Wang,Fu-hao Jiang,Xing-xing Chen,Xin-ran Gao,Ke Fang,Zheng Chen,Jin-fang Ge

doi:10.3389/fnins.2018.00731

Abstract

Chronic stress is a contributing risk factor in the pathogenesis of depression. Although the mechanisms are multifaceted, the relationship can be ascribed partly to stress-related alterations in immune activation and brain plasticity. Considering the increasing evidence regarding the role of Copine 6 in the regulation of synaptic plasticity, the aim of the present study is to investigate Copine 6 expression in the hippocampus and the prefrontal cortex (PFC) in a stress-induced depression rat model. The behavior of the rats was evaluated via the open field test, saccharin preference test, elevated plus maze test, tail suspension test, Morris water maze, and forced swimming test. The plasma concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured, and the protein expressions of brain-derived neurotrophic factor (BDNF), Copine 6, and synaptic plasticity markers in the hippocampus and the PFC were also detected. The results showed that chronic unpredictable mild stress (CUMS) induces depression-like behavior in rats, accompanied by increased plasma concentrations of CRP and IL-6. Moreover, the protein expressions of BDNF, Copine 6, and synapsin I were decreased in both the hippocampus and the PFC of CUMS rats, and the protein expression of synaptotagmin I was decreased in the hippocampus. Furthermore, Pearson’s test revealed a potential relationship between the depression-like behavior, the plasma CRP concentration, and the protein expressions of BDNF, Copine 6, synapsin I, or synaptotagmin I in the hippocampus or the PFC. Together with our previous results, the current findings suggest that apart from immune activation, the BDNF-related imbalance of Copine 6 expression in the brain might play a crucial role in stress-associated depression-like behaviors and synaptic plasticity changes.

Highlights

Depression is one of the most prevalent psychiatric disorders
Our results verified the depression-like behaviors induced by chronic unpredictable mild stress (CUMS) and demonstrated that the protein expressions of brain-derived neurotrophic factor (BDNF), Copine 6, and synapsin I were significantly decreased in both the hippocampus and the prefrontal cortex (PFC) of CUMS rats, together with decreased hippocampal expression of synaptotagmin I
Our results demonstrated the potential relationships among depression-like behavior, imbalanced protein expression in the related brain areas, and increased immune activity

Summary

Introduction

Depression is one of the most prevalent psychiatric disorders. According to the data provided by the World Health Organization, depression affects approximately 350 million individuals in the world. It has been reported that these drugs are not effective in all depressed patients and, even if they are, take weeks to months to produce a response (Berton and Nestler, 2006). Vortioxetine has been reported as a novel antidepressant with multimodal activity and a faster response (Sanchez et al, 2015), targeting the 5-HT3, 5-HT7, 5-HT1, 5-HT1B, and 5-HT1A receptors and the serotonin (5-HT) transporter, this medication requires 8 weeks to reduce the Montgomery–Asberg depression rating scale (MADRS) total score (Mahableshwarkar et al, 2015) and has an adverse event profile similar to that of other selective serotonin reuptake inhibitors (SSRIs) (Zhang et al, 2015). The mechanisms underlying the pathogenesis of depression need to be explored further and new targets for the development of next-generation, rapid-acting antidepressants must be identified (Malinow, 2016; Zanos et al, 2016)

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