Repeated Restraint Stress Led to Cognitive Dysfunction by NMDA Receptor-Mediated Hippocampal CA3 Dendritic Spine Impairments in Juvenile Sprague-Dawley Rats.

Dong-Sheng Sun,Yu Hu,Qian Liu,Xiao Li,Dan Ke,Gong-Ping Liu,Rong-Hong Ma,Gang Zhong,Hong-Xia Cao,Qun Wang,Ting Li,Dan-Ju Luo,Xiao-Yue Hong

doi:10.3389/fnmol.2020.552787

Abstract

Although numerous studies have indicated that chronic stress causes cognitive dysfunction with the impairment of synaptic structures and functions, the relationship between cognitive deficits induced by repeated restraint stress and the level of NMDA receptors in the subregion of the hippocampus has been relatively unknown until now. In this study, 3-week-old male Sprague-Dawley rats were exposed to repeated restraint stress for seven consecutive days, their cognitive functions were evaluated through behavioral tests, and then they were sacrificed for electrophysiological, morphological, and biochemical assays. Chronic repeated restraint stress led to cognitive and electrophysiological impairments, with a reduced density of dendritic spines. We also found that the protein level of NMDA receptors only increased in the hippocampal CA3 region. Nevertheless, repeated restraint stress-induced cognitive and synaptic dysfunction were effectively reversed by Ro25-6981, an inhibitor of the GluN2B receptor. These findings suggest that repeated restraint stress-induced synaptic and cognitive deficits are probably mediated through NMDA receptors.

Highlights

Stress induces dramatic changes in the hippocampal structure and function (McEwen, 2000b; Vyas et al, 2002), as well as severely influences mood and cognitive functions (Kim and Diamond, 2002; de Kloet et al, 2005)
As a major structure of the brain associated with cognition and mood, the hippocampus is extremely susceptible to chronic stress exposure (Lupien et al, 2009)
Some studies have indicated that chronic restraint stress resulted in an increase in glutamate release (Gilad et al, 1990; Lowy et al, 1993), which may trigger the morphologic changes of neuronal synapse related to stress via activation of an NMDA receptor (Magariños and McEwen, 1995)

Summary

Introduction

Stress induces dramatic changes in the hippocampal structure and function (McEwen, 2000b; Vyas et al, 2002), as well as severely influences mood and cognitive functions (Kim and Diamond, 2002; de Kloet et al, 2005). Restraint Stress Induced Cognitive Dysfunction receptors (NMDA-receptor) in the hippocampal CA1 region (Kim et al, 1996; de Kloet et al, 1999; McEwen et al, 2012). Some studies have reported that chronic repeated stress suppressed the neurogenesis in the hippocampal dentate gyrus (DG), reduced hippocampal DG long-term potentiation (LTP), and induced atrophy of hippocampal DG, as well as resulted in shrinkage and debranching of dendrites in the hippocampal CA3 region (McEwen, 2000a; Nasca et al, 2015; Zhou et al, 2018). Chronic restraint stress was reported to induce atrophy of the CA1 hippocampus (Sandi and PineloNava, 2007; Lupien et al, 2009), reduce hippocampal CA1-LTP (Bhagya et al, 2017), and cause apoptosis of neurons and the reduction of dendritic spine density in the hippocampus CA1 region (Huang et al, 2015)

Methods

Results

Conclusion