The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus

Nicole A. Datson*, Niels Speksnijder, Joseph L. Mayer, Peter J. Steenbergen, Oksana Korobko, Jelle Goeman, E. Ronald de Kloet, Marian Joëls, Paul J. Lucassen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

71 Citations (Scopus)

Abstract

The dentate gyrus (DG) of the hippocampus plays a crucial role in learning and memory. This subregion is unique in its ability to generate new neurons throughout life and integrate these new neurons into the hippocampal circuitry. Neurogenesis has further been implicated in hippocampal plasticity and depression. Exposure to chronic stress affects DG function and morphology and suppresses neurogenesis and long-term potentiation (LTP) with consequences for cognition. Previous studies demonstrated that glucocorticoid receptor (GR) blockade by a brief treatment with the GR antagonist mifepristone (RU486) rapidly reverses the stress and glucocorticoid effects on neurogenesis. The molecular pathways underlying both the stress-induced effects and the RU486 effects on the DG are, however, largely unknown. The aim of this study was therefore (1) to investigate by microarray analysis which genes and pathways in the DG are sensitive to chronic stress and (2) to investigate to what extent blockade of GR can normalize these stress-induced effects on DG gene expression. Chronic stress exposure affected the expression of 90 genes in the DG (P <0.01), with an overrepresentation of genes involved in brain development and morphogenesis and synaptic transmission. RU486 treatment of stressed animals affected expression of 107 genes; however, mostly different genes than those responding to stress. Interestingly, we found CREBBP to be normalized by RU486 treatment to levels observed in control animals, suggesting that CREB-signaling may play a central role in mediating the chronic stress effects on neurogenesis, LTP and calcium currents. The identified genetic pathways provide insight into the stress-induced adaptive plasticity of the hippocampal DG that is so central in learning and memory and will direct future studies on the functional outcome and modulation of these stress effects. (C) 2010 Wiley Periodicals, Inc.

Original languageEnglish
Pages (from-to)359-371
Number of pages13
JournalHippocampus
Volume22
Issue number2
DOIs
Publication statusPublished - Feb-2012
Externally publishedYes

Keywords

  • chronic stress
  • glucocorticoid receptor
  • RU486
  • dentate gyrus
  • expression profile
  • ELEMENT-BINDING PROTEIN
  • RUBINSTEIN-TAYBI-SYNDROME
  • ANTAGONIST MIFEPRISTONE NORMALIZES
  • HISTONE ACETYLTRANSFERASE ACTIVITY
  • GENE-EXPRESSION DATA
  • SYNAPTIC PLASTICITY
  • ADULT NEUROGENESIS
  • RAT HIPPOCAMPUS
  • ANTIDEPRESSANT TREATMENT
  • ADRENAL-STEROIDS

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