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The Journal of Neuroscience, September 24, 2003, 23(25):8788-8799
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Cellular/Molecular
Impaired Repression at a 5-Hydroxytryptamine 1A Receptor Gene Polymorphism Associated with Major Depression and Suicide
Sylvie Lemonde,1 Gustavo Turecki,2 David Bakish,3 Lisheng Du,3 Pavel D. Hrdina,3 Christopher D. Bown,1 Adolfo Sequeira,2 Neena Kushwaha,1 Stephen J. Morris,1 Ajoy Basak,4 Xiao-Ming Ou,1 andPaul R. Albert1 1Ottawa Health Research Institute (Neuroscience), University of Ottawa, Departments of Medicine and Cellular and Molecular Medicine, Ottawa, Canada, K1H 8M5, 2Douglas Hospital Research Center, McGill University, Montreal, Canada H4M-1R3, 3Institute for Mental Health Research, Royal Ottawa Hospital, Ottawa, Canada K1Z-7K4, and 4Loeb Research Building, Ottawa Health Research Institute, Ottawa, Canada K1Y-4E9
Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p = 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.
Key words: promoter; polymorphism; major depression; suicide; serotonin; transcription
Received May 2, 2003; revised August 11, 2003; accepted August 12, 2003.
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