Original Article

Molecular Psychiatry (2014) 19, 588–598; doi:10.1038/mp.2013.83; published online 9 July 2013

Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition

J Wei1,4, E Y Yuen1,4, W Liu1, X Li1, P Zhong1, I N Karatsoreos2, B S McEwen3 and Z Yan1

  1. 1Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA
  2. 2Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA
  3. 3Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA

Correspondence: Dr Z Yan, Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, 124 Sherman Hall, 3435 Main Street, Buffalo, NY 14214, USA. E-mail: zhenyan@buffalo.edu

4The first two authors contributed equally to this work.

Received 27 November 2012; Revised 24 April 2013; Accepted 24 May 2013
Advance online publication 9 July 2013

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Abstract

Converging evidence suggests that females and males show different responses to stress; however, little is known about the mechanism underlying the sexually dimorphic effects of stress. In this study, we found that young female rats exposed to 1 week of repeated restraint stress show no negative effects on temporal order recognition memory (TORM), a cognitive process controlled by the prefrontal cortex (PFC), which was contrary to the impairment in TORM observed in stressed males. Concomitantly, normal glutamatergic transmission and glutamate receptor surface expression in PFC pyramidal neurons were found in repeatedly stressed females, in contrast to the significant reduction seen in stressed males. The detrimental effects of repeated stress on TORM and glutamate receptors were unmasked in stressed females when estrogen receptors were inhibited or knocked down in PFC, and were prevented in stressed males with the administration of estradiol. Blocking aromatase, the enzyme for the biosynthesis of estrogen, revealed the stress-induced glutamatergic deficits and memory impairment in females, and the level of aromatase was significantly higher in the PFC of females than in males. These results suggest that estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and PFC-dependent cognition, which may underlie the stress resilience of females.

Keywords:

AMPA receptor; estrogen; NMDA receptor; recognition memory; stress