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.