title: CRE/CREB-driven up-regulation of gene expression by chronic social stress in CRE-luciferase transgenic mice: reversal by antidepressant treatment.
abstract: BACKGROUND
  It 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.
  
  
  RESULTS
  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. 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 (2x10 mg/kg/d) reduced luciferase expression in the hippocampus by 40-50%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Pharmacology, University of Göttingen, Göttingen, Germany. uboeer1@gwdg.de
authors.forename: Ulrike
authors.initials: U
authors.lastname: Böer
authors.forename: Tahseen
authors.initials: T
authors.lastname: Alejel
authors.forename: Stephan
authors.initials: S
authors.lastname: Beimesche
authors.forename: Irmgard
authors.initials: I
authors.lastname: Cierny
authors.forename: Doris
authors.initials: D
authors.lastname: Krause
authors.forename: Willhart
authors.initials: W
authors.lastname: Knepel
authors.forename: Gabriele
authors.initials: G
authors.lastname: Flügge
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001665:Binding Sites; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007099:Imipramine / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D013315:Stress, Psychological; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D017362:Cyclic AMP Response Element-Binding Protein; D008156:Luciferases; D007099:Imipramine