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  • 1
    Keywords: brain ; EXPRESSION ; Germany ; human ; GENE ; transcription ; MICE ; PATIENT ; ACTIVATION ; TRANSCRIPTION FACTOR ; MARKER ; PHOSPHORYLATION ; ASSOCIATION ; polymorphism ; CAMP ; ELEMENT-BINDING PROTEIN ; PATTERNS ; CYCLIC-AMP ; molecular ; PATTERN ; LIGHT ; analysis ; MEDICINE ; CIRCADIAN CLOCK ; MAJOR DEPRESSION ; SUPRACHIASMATIC-NUCLEI
    Abstract: Activation of the transcription factor CREB by Ser142 phosphorylation is implicated in synchronizing circadian rhythmicity, which is disturbed in many depressive patients. Hence, one could assume that emotional behaviour and neuroendocrinological markers would be altered in CREBS142A mice, in which serine 142 is replaced by alanine, preventing phosphorylation at this residue. Moreover, associations of CREB Ser142 and seasonal affective disorder (SAD) might be detectable by the analysis of single-nucleotide polymorphisms (SNPs) in the CREB gene close to the Ser142 residue in SAD patients. However, neither CREBS142A mice demonstrate features of depression, nor there is evidence for an association of SAD with the CREB genotypes. Nevertheless, in humans there is an association of a global seasonality score and circadian rhythmicity with the CREB genotypes in healthy control probands, but not SAD patients. This parallels the phenotype of CREBS142A mice, presenting alterations of circadian rhythm and light-induced entrainment. Thus it is reasonable to assume that CREB Ser142 represents a molecular switch in mice and men, which is responsible for the (dys)regulation of circadian rhythms. (C) 2007 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17574346
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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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