Increased serotonin-1A (5-HT1A) autoreceptor expression and reduced raphe serotonin levels in deformed epidermal autoregulatory factor-1 (Deaf-1) gene knock-out mice.
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 knock-out 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.
Ottawa Hospital Research Institute, Neuroscience, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Margaret
M
Czesak
Brice
B
Le François
Anne M
AM
Millar
Mariam
M
Deria
Mireille
M
Daigle
Jane E
JE
Visvader
Hymie
H
Anisman
Paul R
PR
Albert
D000818:Animals; D017660:Autoreceptors / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D003866:Depressive Disorder / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011903:Raphe Nuclei / Q000502:physiology*; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
D017660:Autoreceptors; D004268:DNA-Binding Proteins; C548809:Deaf1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase