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

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.

Sex and chronic stress alter the distribution of glutamate receptors within rat hippocampal CA3 pyramidal cells following oxycodone conditioned place preference

“…In both sexes, the total number of GluN1 subunits increased in CA3 dendrites following CIS. Our data echoes the findings of others ( Sun et al, 2020 ), who showed that the total protein and mRNA levels of GluN1, GluN2A, and GluN2B were significantly increased in the CA3 region of the hippocampus in male Sprague Dawley rats exposed to repeated restraint stress (RRS) when compared to control. Additionally, the same experiment showed that the dendritic spine density in the CA3 region significantly decreased and that LTP was attenuated in male rats exposed to RRS ( Sun et al, 2020 ).…”

“…Using in vivo microdialysis, it has been previously demonstrated that ten days of RRS results in lower glutamate levels in the male rat hippocampus compared to unstressed controls ( Macht et al, 2020 ). Even though prior studies have shown that RRS reduces glutamate levels in the male rat hippocampus, our study offers a different perspective by suggesting that the increase in GluN1 in all cellular compartments in male rats following CPP behaviors and CIS potentially increases the availability of receptors to bind glutamate, similar to Sun et al (2020) . Such a process may impact the lack of opioid receptor redistribution seen in our prior experiments in CIS males ( Reich et al, 2019 ).…”

“…Previous studies have analyzed the effect of RRS on both NMDA receptor protein levels and glutamate levels. RRS results in an increase in NMDA receptor protein level in the male rat hippocampus ( Sun et al, 2020 ). Using in vivo microdialysis, it has been previously demonstrated that ten days of RRS results in lower glutamate levels in the male rat hippocampus compared to unstressed controls ( Macht et al, 2020 ).…”

The Protective Effects of Crocin on Input-Output Functions and Long-term Potentiation of Hippocampal CA1 Area in Rats Exposed to Chronic Social Isolated Stress

“…Also, chronic isolation stress increased the corticosterone levels in both hippocampus and frontal cortex, whereas the glucose levels did not change in both these regions. In this way, some previous reports demonstrated the role of stress on impairments of excitability and long-term plasticity in other hippocampal regions (Artola, 2008;Radahmadi et al, 2014;Sun et al, 2020) and even with another type of stress (Hosseini Dastgerdi et al, 2021). Moreover, different factors affect the brain functions in stress conditions such as the severity, period and pattern, and nature of stressors (Radahmadi et al, 2015).…”

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

“…Stress is known to evoke cognitive and emotional deficits [123]. In particular, stressinduced cognitive defects are attributable to the dysfunction of hippocampal channels or receptors [123,124]. Li et al reported that, in rats, acute stress led to cognitive failure, accompanied by the downregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the hippocampal CA1 region [120], as well as significant decreases in the expression of PGC-1α, β-catenin, E4 promoter-binding protein 4 (E4BP4), and USP2.…”