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)
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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: | https://repository.cshl.edu/id/eprint/27673 |
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