Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions

Ridder, S., Chourbaji, S., Hellweg, R., Urani, A., Zacher, C., Schmid, W., Zink, M., Hortnagl, H., Flor, H., Henn, F. A., Schutz, G., Gass, P. (June 2005) Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions. J Neurosci, 25 (26). pp. 6243-50. ISSN 1529-2401 (Electronic)0270-6474 (Linking)

[img]
Preview
PDF (Paper)
Henn J Neurosci 2005.pdf - Published Version

Download (405Kb) | Preview
URL: http://www.ncbi.nlm.nih.gov/pubmed/15987954
DOI: 10.1523/jneurosci.0736-05.2005

Abstract

Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/- mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/- mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression.

Item Type: Paper
Uncontrolled Keywords: Animals Brain-Derived Neurotrophic Factor/metabolism Conditioning, Classical Corticosterone/blood Depressive Disorder/ genetics Dexamethasone/diagnostic use Electroshock Fear Helplessness, Learned Hippocampus/ physiology/physiopathology Housing, Animal Mice Mice, Mutant Strains Models, Neurological Nerve Growth Factors/metabolism Receptors, Glucocorticoid/ genetics/physiology Stress, Psychological/ genetics
Subjects: diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
diseases & disorders > mental disorders
diseases & disorders > mental disorders > mood disorders
organism description > animal
diseases & disorders > mental disorders > mood disorders > depression
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > transgenic animal
CSHL Authors:
Communities: CSHL labs > Henn lab
Depositing User: Matt Covey
Date: 29 June 2005
Date Deposited: 01 Mar 2013 21:48
Last Modified: 01 Mar 2013 21:48
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27673

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving