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  • 1
    Keywords: RECEPTOR ; MODEL ; GENE ; MICE ; ACTIVATION ; RAT ; RATS ; WATER ; MEMORY ; hippocampus ; LONG-TERM POTENTIATION ; synaptic plasticity ; WATER MAZE ; hormone ; DISRUPTION ; MODULATION ; WILD-TYPE ; glucocorticoid receptor ; RECEPTORS ; RAT-BRAIN ; MEMORY IMPAIRMENT ; ABSENCE ; TARGETED DISRUPTION ; development ; mineralocorticoid receptor ; MUTANTS ; HORMONES ; GLUCOCORTICOIDS ; RECEPTOR GENE ; REACTIVITY ; STRATEGY ; glucocorticoid ; GLUCOCORTICOID RECEPTORS ; Behavioral Reactivity ; Impairment of Hippocampal Function ; II CORTICOSTEROID RECEPTORS ; DAY-OLD CHICKS ; ELECTROCONVULSIVE SHOCK ; SELECTIVE IMPAIRMENT ; HIPPOCAMPAL-LESIONS
    Abstract: 0140,english,Previous studies in rats using the Morris water maze suggested that the processing of spatial information is modulated by corticosteroid hormones through mineralocorticoid and glucocorticoid receptors in the hippocampus. Mineralocorticoid receptors appear to be involved in the modulation of explorative behaviour, while additional activation of glucocorticoid receptors facilitates the storage of information. In the present study we used the water maze task to examine spatial learning and memory in mice homozygous and heterozygous for a targeted disruption of the glucocorticoid receptor gene. Compared with wild-type controls, homozygous and heterozygous mice were impaired in the processing of spatial but not visual information. Homozygous mutants performed variably during training, without specific platform-directed search strategies. The spatial learning disability was partly compensated for by increased motor activity. The deficits were indicative of a dysfunction of glucocorticoid receptors as well as of mineralocorticoid receptors. Although the heterozygous mice performed similarly to wild-type mice with respect to latency to find the platform, their strategy was more similar to that of the homozygous mice. Glucocorticoid receptor-related long-term spatial memory was impaired. The increased behavioural reactivity of the heterozygous mice in the open field points to a more prominent mineralocorticoid receptor- mediated function. The findings indicate that (i) the glucocorticoid receptor is of critical importance for the control of spatial behavioural functions, and (ii) mineralocorticoid receptor-mediated effects on this behaviour require interaction with functional glucocorticoid receptors. Until the development of site-specific, inducible glucocorticoid receptor mutants, glucocorticoid receptor-knockout mice present the only animal model for the study of corticosteroid-mediated effects in the complete absence of a functional receptor
    Type of Publication: Journal article published
    PubMed ID: 9464923
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  • 2
    Keywords: brain ; RECEPTOR ; EXPRESSION ; Germany ; MODEL ; MODELS ; SYSTEM ; EXPOSURE ; GENE ; PROTEIN ; MICE ; PATIENT ; MECHANISM ; MESSENGER-RNA ; RECEPTOR EXPRESSION ; chromosome ; MOUSE ; TRANSGENIC MICE ; hormone ; YEAST ; STRESS ; PATHOGENESIS ; DNA-BINDING ; Jun ; glucocorticoid receptor ; sensitivity ; BEHAVIOR ; OVEREXPRESSION ; GLUCOCORTICOID-RECEPTOR ; signaling ; molecular ; regulation ; KNOCKOUT MICE ; NEUROTROPHIC FACTOR ; FOREBRAIN ; RAT HIPPOCAMPUS ; depression ; DEXAMETHASONE-CRH TEST ; helplessness
    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% GRgene dose reduction, and (2) mice overexpressingGR 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
    Type of Publication: Journal article published
    PubMed ID: 15987954
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  • 3
    Keywords: EXPRESSION ; IN-VITRO ; SURVIVAL ; MODEL ; GENE-EXPRESSION ; MICE ; ACTIVATION ; MAP KINASE ; DNA-BINDING ; KAPPA-B ; REPRESSION ; INFLAMMATORY RESPONSES ; dexamethasone ; CLP ; GR ; IL-1 beta ; PHOSPHATASE-1
    Abstract: Sepsis is controlled by endogenous glucocorticoids (GCs). Previous studies provided evidence that crosstalk of the monomeric GC receptor (GR) with proinflammatory transcription factors is the crucial mechanism underlying the suppressive GC effect. Here we demonstrate that mice with a dimerization-deficient GR (GR(dim)) are highly susceptible to sepsis in 2 different models, namely cecal ligation and puncture and lipopolysaccharide (LPS)-induced septic shock. TNF-alpha is normally regulated in these mice, but down-regulation of IL-6 and IL-1 beta is diminished. LPS-treated macrophages derived from GR(dim) mice are largely resistant to GC actions in vitro in terms of morphology, surface marker expression, and gene expression. Treatment with recombinant IL-1 receptor antagonist improved survival of GR(dim) mice and mice lacking the GR in macrophages (GR(LysMCre)) mice. This suggests that regulation of IL-1 beta in macrophages by GCs is pivotal to control sepsis.-Kleiman, A., Hubner, S., Rodriguez Parkitna, J. M., Neumann, A., Hofer, S., Weigand, M. A., Bauer, M., Schmid, W., Schutz, G., Libert, C., Reichardt, H. M., Tuckermann, J. P. Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages.
    Type of Publication: Journal article published
    PubMed ID: 22042221
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  • 4
    Keywords: RECEPTOR ; GROWTH ; CELL ; Germany ; IN-VIVO ; MODEL ; VIVO ; SUPPORT ; liver ; GENE ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; transcription ; MICE ; ACTIVATION ; TRANSCRIPTION FACTOR ; REDUCTION ; hepatocytes ; TRANSCRIPTION FACTORS ; hormone ; inactivation ; DNA-BINDING ; REGION ; REGIONS ; TARGETED DISRUPTION ; BINDING PROTEIN-3 ; I IGF-I ; postnatal body growth,glucocorticoid receptor,growth hormone signaling,Stat5 ; STAT5B
    Abstract: Mice carrying a hepatocyte-specific inactivation of the glucorticoid receptor (GR) gene show a dramatic reduction in body size. Growth hormone signaling mediated by the Stat5 transcription factors is impaired. We show that Stat5 proteins physically interact with GR and GR is present in vivo on Stat5-dependent IGF-I and ALS regulatory regions. Interestingly, mice with a DNA-binding-deficient GR but an unaltered ability to interact with STAT5(GR(dim/dim)) have a normal body size and normal levels of Stat5-dependent mRNAs. These findings strongly support the model in which GR acts as a coactivator for Stat5-dependent transcription upon GH stimulation and reveal an essential role of hepatic GR in the control of body growth
    Type of Publication: Journal article published
    PubMed ID: 15037546
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