Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex

Neuron. 2012 Mar 8;73(5):962-77. doi: 10.1016/j.neuron.2011.12.033.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Analysis of Variance
  • Animals
  • Bicuculline / pharmacology
  • Cognition Disorders / etiology*
  • Cognition Disorders / pathology*
  • Disease Models, Animal
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • F-Box Proteins / metabolism
  • GABA-A Receptor Antagonists
  • Immunoprecipitation
  • In Vitro Techniques
  • Male
  • Nedd4 Ubiquitin Protein Ligases
  • Neuropsychological Tests
  • Prefrontal Cortex* / metabolism
  • Prefrontal Cortex* / pathology
  • Prefrontal Cortex* / physiopathology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiopathology*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism*
  • Recognition, Psychology
  • Restraint, Physical / adverse effects
  • Stress, Psychological / complications*
  • Stress, Psychological / pathology
  • Ubiquitin-Protein Ligases / metabolism


  • Endosomal Sorting Complexes Required for Transport
  • Excitatory Amino Acid Antagonists
  • F-Box Proteins
  • GABA-A Receptor Antagonists
  • RNA, Small Interfering
  • Receptors, Glutamate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-Amino-5-phosphonovalerate
  • NEDD4L protein, rat
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, rat
  • Ubiquitin-Protein Ligases
  • Bicuculline