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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 and Paul 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

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Received May 2, 2003; revised August 11, 2003; accepted August 12, 2003.

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