Neuron - Repeated Stress Causes Cognitive Impairment by Suppressing Glutamate Receptor Expression and Function in Prefrontal Cortex

Neuron - Repeated Stress Causes Cognitive Impairment by Suppressing Glutamate Receptor Expression and Function in Prefrontal Cortex

Neuron, Volume 73, Issue 5, 962-977, 8 March 2012
Copyright 2012 Elsevier Inc. All rights reserved.
10.1016/j.neuron.2011.12.033

Authors

Eunice Y. Yuen, Jing Wei, Wenhua Liu, Ping Zhong, Xiangning Li, Zhen YanSee Affiliations

• Hint: Rollover Authors and Affiliations

Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA Corresponding author These authors contributed equally to this work

• Highlights
► Repeated stress impairs PFC-dependent recognition memory ► Repeated stress depresses PFC glutamatergic transmission in juvenile male rats ► Repeated stress increases GluR1 and NR1 ubiquitination and degradation in PFC ► Nedd4 and Fbx2 are the E3 ubiquitin ligases involved in the stress effects in PFC

Summary

Chronic stress could trigger maladaptive changes associated with stress-related mental disorders; however, the underlying mechanisms remain elusive. In this study, we found that exposing juvenile male rats to repeated stress significantly impaired the temporal order recognition memory, a cognitive process controlled by the prefrontal cortex (PFC). Concomitantly, significantly reduced AMPAR- and NMDAR-mediated synaptic transmission and glutamate receptor expression were found in PFC pyramidal neurons from repeatedly stressed animals. All these effects relied on activation of glucocorticoid receptors and the subsequent enhancement of ubiquitin/proteasome-mediated degradation of GluR1 and NR1 subunits, which was controlled by the E3 ubiquitin ligase Nedd4-1 and Fbx2, respectively. Inhibition of proteasomes or knockdown of Nedd4-1 and Fbx2 in PFC prevented the loss of glutamatergic responses and recognition memory in stressed animals. Our results suggest that repeated stress dampens PFC glutamatergic transmission by facilitating glutamate receptor turnover, which causes the detrimental effect on PFC-dependent cognitive processes.