Transcriptional regulation at a HTR1A polymorphism associated with mental illness.
The serotonin-1A (5-HT1A) receptor serves as a hub to regulate the activity and actions of the serotonin system, and is expressed both as a presynaptic autoreceptor on raphe neurons, and as a major postsynaptic receptor in hippocampal, cortical, and hypothalamic regions involved in mood, emotion and stress response. As such, the level of expression of 5-HT1A receptors is implicated in the development of anxiety and depression phenotypes. This review focuses on the C(-1019)G (rs6295) promoter polymorphism of the 5-HT1A receptor gene (HTR1A) and its effect on the activity of transcription factors that recognize the C-allele, including Deaf-1, Hes1 and Hes5; its effects on 5-HT1A receptor expression in pre- and postsynaptic areas; as well as its implication in early postnatal development and adult neurogenesis in the hippocampus and cortex. Although several studies have now replicated the association of the G-allele with depression, panic disorder, neuroticism, and reduced response to antidepressant or antipsychotic treatment, ethnic, disease and genetic heterogeneity among subjects in different studies may obscure such associations. Gene-gene interaction studies suggest that the 5-HT1A receptor G(-1019) allele is a risk allele which could be used as a marker for depression and related mood disorders. Finally, association of the G(-1019) allele with increased raphe 5-HT1A binding potential, increased amygdala reactivity to emotional stimuli, and reduced amygdala volume, particularly in disease states, suggests a functional role for the C(-1019)G site in 5-HT1A receptor dys-regulation and predisposition to mental illness.
Le François
Brice
B
Ottawa Health Research Institute (Neuroscience), University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.
Czesak
Margaret
M
Steubl
Dominik
D
Albert
Paul R
PR
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D001523:Mental Disorders / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*
D000928:Antidepressive Agents; D044282:Receptor, Serotonin, 5-HT1A