S-Ketamine Exerts Antidepressant Effects by Regulating Rac1 GTPase Mediated Synaptic Plasticity in the Hippocampus of Stressed Rats.

Hongbai Wang,Fan Zhang,Xianlin Zhu,Dawei Liu,Rongyu Zhu,Su Yuan,Zaiping Wang,Fuxia Yan,Yufeng You,Banglin Wu

doi:10.1007/s10571-021-01180-6

Abstract

Clinical studies have found that ketamine has a rapid and lasting antidepressant effect, especially in the case of patients with major depressive disorder (MDD). The molecular mechanisms, however, remain unclear. In this study, we observe the effects of S-Ketamine on the expression of Rac1, neuronal morphology, and synaptic transmission function in the hippocampus of stressed rats. Chronic unpredictable mild stress (CUMS) was used to construct stressed rats. The rats were given a different regimen of ketamine (20mg/kg, i.p.) and Rac1 inhibitor NSC23766 (50µg, ICV) treatment. The depression-like behavior of rats was evaluated by sucrose preference test and open-field test. The protein expression of Rac1, GluA1, synapsin1, and PSD95 in the hippocampus was detected by Western blot. Pull-down analysis was used to examine the activity of Rac1. Golgi staining and electrophysiological study were used to observe the neuronal morphology and long-term potentiation (LTP). Our results showed that ketamine can up-regulate the expression and activity of Rac1; increase the spine density and the expression of synaptic-related proteins such as GluA1, Synapsin1, and PSD95 in the hippocampus of stressed rats; reduce the CUMS-induced LTP impairments; and consequently improve depression-like behavior. However, Rac1 inhibitor NSC23766 could have effectively reversed ketamine-mediated changes in the hippocampus of rats and counteracted its antidepressant effects. The specific mechanism of S-Ketamine's antidepressant effect may be related to the up-regulation of the expression and activity of Rac1 in the hippocampus of stressed rats, thus enhancing synaptic plasticity.

Highlights

Depression is a common psychiatric illness with high morbidity and disability rates, resulting in enormous public health costs and personal suffering (Gu et al 2013)
Sucrose preference percentage (SPP) can accurately assess the degree of anhedonia in rats (Luo et al 2010), and we used it to validate the Chronic unpredictable mild stress (CUMS) model and the antidepressant effect of s-ketamine
The post hoc tests showed that the SPP in the CUMS-treated groups was significantly lower than that of the group C (P < 0.001, respectively), but no statistical difference was observed between the four CUMS-treated groups (P = 1.000, respectively)

Summary

Introduction

Depression is a common psychiatric illness with high morbidity and disability rates, resulting in enormous public health costs and personal suffering (Gu et al 2013). Due to the lack of conventional and effective antidepressants, the relapse rate of patients with first-onset depression is as high as 50% within the first 5 years, and the lifetime prevalence reaches 15%~20% (Angst et al 2013). Traditional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and stricyclic antidepressants, usually have slow onset for therapeutic response (takes several weeks) and a low remission rate (40%~50%) (Cipriani et al 2016; Sinyor et al 2010). Clinical studies have found that the intravenous anesthetic ketamine has a rapid and lasting antidepressant effect, especially for patients with MDD and who are treatment-resistant or show poor response to SSRIs (Wang et al 2012; Cornwell et al 2012). The underlying molecular mechanism of ketamine's antidepressant effect remains poorly understood

Methods

Results

Conclusion