Increased Serotonin-1A (5-HT1A) Autoreceptor Expression and Reduced Raphe Serotonin Levels in Deformed Epidermal Autoregulatory Factor-1 (Deaf-1) Gene Knock-out Mice
- Author(s)
- Czesak, M; Le Francois, B; Millar, AM; Deria, M; Daigle, M; Visvader, JE; Anisman, H; Albert, PR;
- Details
- Publication Year 2012-02-24,Volume 287,Issue #9,Page 6615-6627
- Journal Title
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Publication Type
- Journal Article
- Abstract
- Altered regulation of the serotonin-1A (5-HT1A) receptor gene is implicated in major depression and mood disorders. The functional human 5-HT1A C(-1019) G promoter polymorphism (rs6295), which prevents the binding of Deaf-1/NUDR leading to dysregulation of the receptor, has been associated with major depression. In cell models Deaf-1 displays dual activity, repressing 5-HT1A autoreceptor expression in serotonergic raphe cells while enhancing postsynaptic 5-HT1A heteroreceptor expression in nonserotonergic neurons. A functional Deaf-1 binding site on the mouse 5-HT1A promoter was recognized by Deaf-1 in vitro and in vivo and mediated dual activity of Deaf-1 on 5-HT1A gene transcription. To address regulation by Deaf-1 in vivo, Deaf-1 knock-out mice bred to a C57BL/6 background were compared with wild-type siblings for changes in 5-HT1A RNA and protein by quantitative RT-PCR, in situ hybridization, and immunofluorescence. In the dorsal raphe, Deaf-1 knockout mice displayed increased 5-HT1A mRNA, protein, and 5-HT1A-positive cell counts but reduced 5-HT levels, whereas other serotonergic markers, such as tryptophan hydroxylase (TPH)- or 5-HT-positive cells and TPH2 RNA levels, were unchanged. By contrast, 5-HT1A mRNA and 5-HT1A-positive cells were reduced in the frontal cortex of Deaf-1-null mice, with no significant change in hippocampal 5-HT1A RNA, protein, or cell counts. The region-specific alterations of brain 5-HT1A gene expression and reduced raphe 5-HT content in Deaf-1(-/-) mice indicate the importance of Deaf-1 in regulation of 5-HT1A gene expression and provide insight into the role of the 5-HT1A G(-1019) allele in reducing serotonergic neurotransmission by derepression of 5-HT1A autoreceptors.
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Keywords
- POSITRON-EMISSION-TOMOGRAPHY; MAJOR DEPRESSIVE DISORDER; 1A RECEPTOR GENE; RAT-BRAIN; HIPPOCAMPAL NEUROGENESIS; ANTIDEPRESSANT-TREATMENT; CHRONIC FLUOXETINE; TREATMENT RESPONSE; MESSENGER-RNA; BINDING
- Research Division(s)
- Stem Cells And Cancer
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307310/
- Publisher's Version
- https://doi.org/10.1074/jbc.M111.293027
- Terms of Use/Rights Notice
- Copyright © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
Creation Date: 2012-02-24 12:00:00