Transcriptional regulation at a HTR1A polymorphism associated with mental illness

Neuropharmacology. 2008 Nov;55(6):977-85. doi: 10.1016/j.neuropharm.2008.06.046. Epub 2008 Jun 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Gene Expression Regulation / physiology*
  • Gene Expression Regulation / radiation effects
  • Genetic Predisposition to Disease*
  • Humans
  • Mental Disorders / genetics*
  • Mental Disorders / pathology
  • Polymorphism, Genetic / genetics*
  • Receptor, Serotonin, 5-HT1A / genetics*


  • Antidepressive Agents
  • Receptor, Serotonin, 5-HT1A