Eunice Y. Yuen, State University of New York, Buffalo, USA, and colleagues 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).

AMPAR is a receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS), NMDAR is a glutamate receptor that is the predominant molecular device for controlling synaptic plasticity and memory function. In PFC pyramidal neurons from repeatedly stressed animals, significantly reduced AMPAR- and NMDAR-mediated synaptic transmission and glutamate receptor expression were found. These effects relied on activation of glucocorticoid receptors and the subsequent enhancement of ubiquitin/proteasome-mediated degradation of GluR1 and NR1 subunits. This 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.

The results suggest that repeated stress dampens PFC glutamatergic transmission by facilitating glutamate receptor turnover. This causes the detrimental effect on PFC-dependent cognitive processes. The brain of juvenile is more sensitive to repeated stress, as their PFC still is developing.

• Repeated Stress Causes Cognitive Impairment by Suppressing Glutamate Receptor Expression and Function in Prefrontal Cortex,
  Eunice Y. Yuen, Jing Wei, Wenhua Liu, Ping Zhong, Xiangning Li, Zhen Yan,
  Neuron 2012.
  DOI: 10.1016/j.neuron.2011.12.033