Abstract
BackgroundIt has been suggested that stress provokes neuropathological changes and may thus contribute to the precipitation of affective disorders such as depression. Likewise, the pharmacological therapy of depression requires chronic treatment and is thought to induce a positive neuronal adaptation, presumably based on changes in gene transcription. The transcription factor cAMP-responsive element binding protein (CREB) and its binding site (CRE) have been suggested to play a major role in both the development of depression and antidepressive therapy.Methodology/Principle FindingsTo investigate the impact of stress and antidepressant treatment on CRE/CREB transcriptional activity, we generated a transgenic mouse line in which expression of the luciferase reporter gene is controlled by four copies of CRE. In this transgene, luciferase enzyme activity and protein were detected throughout the brain, e.g., in the hippocampal formation. Chronic social stress significantly increased (by 45 to 120%) CRE/CREB-driven gene expression measured as luciferase activity in several brain regions. This was also reflected by increased CREB-phosphorylation determined by immunoblotting. Treatment of the stressed mice with the antidepressant imipramine normalized luciferase expression to control levels in all brain regions and likewise reduced CREB-phosphorylation. In non-stressed animals, chronic (21 d) but not acute (24 h) treatment with imipramine (2×10 mg/kg/d) reduced luciferase expression in the hippocampus by 40–50%.Conclusions/SignificanceOur results emphasize a role of CREB in stress-regulated gene expression and support the view that the therapeutic actions of antidepressants are mediated via CRE/CREB-directed transcription.
Highlights
Depression is a prevalent mood disorder with a high incidence
Our results indicate that cAMP responsive element (CRE)/ cAMP-responsive element binding protein (CREB)-directed gene transcription is enhanced by chronic psychosocial stress and that treatment with imipramine reverses the stress-induced effect on CREB activation in vivo
In this study we determined the effect of chronic psychosocial stress and of imipramine treatment on the transcriptional activity of CREB in vivo
Summary
Depression is a prevalent mood disorder with a high incidence. Though the etiology of depressive diseases is not yet fully understood, there is evidence that besides genetic factors[1] environmental influences such as stressful life events are involved in its development[2]. There is a clear discrepancy between antidepressants rapidly increasing extracellular monoamine concentrations and the lack of immediate clinical efficacy in that antidepressive effects usually occur only with a delay of two to three weeks This lag phase has been considered to be related to drug-induced neuronal plasticity and may be explained at the molecular level by changes in gene expression[6]. To investigate the impact of stress and antidepressant treatment on CRE/CREB transcriptional activity, we generated a transgenic mouse line in which expression of the luciferase reporter gene is controlled by four copies of CRE. Our results emphasize a role of CREB in stress-regulated gene expression and support the view that the therapeutic actions of antidepressants are mediated via CRE/CREB-directed transcription
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