Research ArticleDownregulation of Egr-1 Expression Level via GluN2B Underlies the Antidepressant Effects of Ketamine in a Chronic Unpredictable Stress Animal Model of Depression
Introduction
Depression is a severe, debilitating, and recurring psychiatric disorder that affects approximately 17% of the population (Kessler et al., 2003). However, its pathological mechanism is unclear. Preclinical and clinical studies have demonstrated that a single subanesthetic dose of ketamine, which is a noncompetitive N-methyl-D-aspartate receptor (NDMAR) antagonist, produces rapid and effective antidepressant effects (Berman et al., 2000, Mathew et al., 2012) by rapidly reversing the decreases in the postsynaptic density protein 95 (PSD-95) expression level and spine density (Liu et al., 2016), which promotes synaptic plasticity. However, it is unclear how suppression of NMDARs produces these beneficial effects. Revealing the cellular signaling mechanisms underlying the antidepressant effects of ketamine will promote the development of new treatment regime with enhanced beneficial actions and minimized side effects.
The PSD is composed of cytoskeletal proteins, membrane receptors and cellular adhesion proteins as well as signaling molecules that are located at the head of the spine (Chen et al., 2005). The PSD plays a key role in signal transduction and synaptic plasticity that underlies the processes of memory, emotion, and learning (Luscher et al., 2000). Protein synthesis, degradation and trafficking regulate the biochemical and structural changes in the PSD (Bao et al., 2004); however, the precise mechanisms are incompletely understood.
Early growth response 1 (Egr-1) is a zinc finger transcription factor that modulates the expression of genes that have diverse cellular function, such as cell proliferation, cell growth, and learning. Egr-1 is a Ca2+-dependent transcription factor and the elevation of intracellular Ca2+ is the key stimulator (Thiel et al., 2010). The N-methyl-D-aspartate receptor (NMDAR), a glutamate-gated Ca2+ channel, is the main activator of Egr-1 in the CNS (Cole et al., 1989). Recently, a study proved that the activation of NMDAR recruits Egr-1 to the PSD95 promoter and represses the transcription of the PSD-95 gene (Qin et al., 2015).
It is well known that the excessive accumulation of extracellular glutamate has neurotoxic effects and underlies the onset of depression (Deutschenbaur et al., 2016). Therefore, we speculate that the overactivation of NMDARs by elevated glutamate suppresses the transcription of the PSD-95 gene and damages synaptic plasticity by recruiting Egr-1 to the PSD-95 promoter, which is involved in the pathogenesis of depression.
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Animals and drugs
All animal experiments were performed using C57BL/6 male mice and performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (USA). The study protocol was approved by the Institutional Animal Care Committee of Weifang Medical University, Weifang, China. The mice were purchased from the animal center of Weifang Medical University, Weifang, China and were housed at a constant temperature (22 ± 1 °C) and humidity with food and water available ad
Ketamine and Ro-25-6981 attenuated depression-like behaviors in the CUS animal model
The experimental design is illustrated in Fig. 1A. We assessed the effects of different treatments on depression-related behaviors (Fig. 1B–D). An ANOVA suggested that there were significant differences between the groups in the FST [F(4,55) = 26.119, P < 0.01, Fig. 1D] and the time spent in center in the OFT [F(4,55) = 37.324, P < 0.01, Fig. 1C] but not in the total distance in the OFT [F(4,55) = 0.513, P > 0.05, Fig. 1A].
In the OFT and FST, Tukey’s analyses revealed that CUS significantly
Discussion
The present study provided the evidence of the downregulation of the hippocampal Egr-1 expression level, in which GluN2B may play an important role in the antidepressant effects of ketamine in the CUS animal model. These results indicated that the CUS exposure induced depression-like behaviors along with damage to synaptic plasticity in the hippocampus. These behavioral and molecular alterations caused by CUS were restored by a single administration of ketamine, GluN2B antagonist, or Egr-1
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