Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice.

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RESEARCH PRODUCT

Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice.

Hongyin Lin Christoph Hiemke Annette Heinrich Willhart Knepel Georg Mayr Irmgard Cierny Doris Krause Ulrike Böer

subject

Male Transcriptional Activation Bipolar Disorder Transgene Down-Regulation Mice Transgenic CREB Drug Administration Schedule 03 medical and health sciences Glycogen Synthase Kinase 3 Mice 0302 clinical medicine GSK-3 Transcription (biology)Antimanic Agents Genes Reporter Gene expression Animals Phosphorylation Protein kinase A Cyclic AMP Response Element-Binding Protein Social Behavior Transcription factor 030304 developmental biology Pharmacology 0303 health sciences Reporter gene biology Behavior Animal Brain Molecular biology Up-Regulation Psychiatry and Mental health Disease Models Animal Gene Expression Regulation Chronic Disease biology.protein Lithium Compounds 030217 neurology & neurosurgery Stress Psychological Adenylyl Cyclases Signal Transduction

description

The molecular mechanism of action of the mood stabilizer lithium is assumed to involve changes in gene expression leading to neuronal adaptation. The transcription factor CREB (cAMP-responsive element binding protein) regulates the expression of many genes and has been implicated in important brain functions and the action of psychogenic agents. We here investigated the effect of lithium on cAMP-responsive element (CRE)/CREB-mediated gene transcription in the brain, using transgenic reporter mice that express the luciferase reporter gene under the control of four copies of the rat somatostatin gene promoter CRE. Chronic (21 days) but not acute (24 h) treatment with lithium (7.5 mmol/kg) significantly decreased CRE/CREB-directed gene expression in hippocampus, cortex, hypothalamus, and striatum to 60-70%, and likewise reduced CREB phosphorylation. As bipolar disorder is also considered as a stress-related disorder, the effect of lithium was determined in mice submitted to a paradigm for chronic psychosocial stress. As shown before, stress for 25 days significantly increased CRE/CREB-directed gene expression in several brain regions by 100-150%. Treatment of stressed mice with lithium decreased stress-induced CRE/CREB-directed gene expression to control levels in nearly all brain regions and likewise reduced CREB phosphorylation. Chronic lithium treatment induced beta-catenin accumulation and decreased cAMP levels, indicating an inhibitory effect of lithium on glycogen synthase kinase 3 and the adenylate cyclase/protein kinase A signalling cascade, which are known to modulate CREB activity. We here for the first time show that lithium regulates CRE/CREB-directed gene transcription in vivo and suggest CREB as a putative mediator of the neuronal adaptation after chronic lithium treatment.

year	journal	country	edition	language
2007-11-28	Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

10.1038/sj.npp.1301640 https://pubmed.ncbi.nlm.nih.gov/18046304