Mice with Genetically Altered Glucocorticoid Receptor Expression Show Altered Sensitivity for Stress-Induced Depressive Reactions
Open accessAbstract
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.
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Selective knockdown of GR expression in the corticolimbic system in rodents is associated with increased HPA activity under basal and stressful conditions.
“Thus, selective knockdown of GR expression in the corticolimbic system in rodents is associated with increased HPA activity under basal as well as stressful conditions.125”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [125]
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- Authors
- Ridder, S., Chourbaji, S., Hellweg, R., Urani, A., Zacher, C., Schmid, W., Zink, M., Hörtnagl, H., Flor, H., Henn, F. A., Schütz, G., & Gass, P.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Gass, Peter
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-06-29
- Volume
- 25
- Issue
- 26
- Pages
- 6243-6250
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725059
- OpenAlex
- W2148316222
- Cited by
- 382
- References
- 6
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 11 · 2021: 12 · 2020: 12 · 2019: 18 · 2018: 14 · 2017: 25 · 2016: 27 · 2015: 18 · 2014: 27 · 2013: 28 · 2012: 36
- FWCI
- 9.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Alexander von Humboldt-Stiftung
- Deutsche Forschungsgemeinschaft (SFB405, SFB 636)
- Universität Heidelberg
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- glucocorticoid receptor, major depressive disorder, hypothalamic-pituitary-adrenal axis, dexamethasone/corticotropin-releasing hormone test, stress tolerance, brain-derived neurotrophic factor, hippocampus, mouse model of depression
- MeSH terms
- Animals, Conditioning, Classical, Corticosterone, Depressive Disorder, Dexamethasone, Electroshock, Fear, Helplessness, Learned, Hippocampus, Housing, Animal, Mice, Mutant Strains, Models, Neurological, Nerve Growth Factors, Receptors, Glucocorticoid, Stress, Psychological, Brain-Derived Neurotrophic Factor, Mice
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