5-HT1A receptors, gene repression, and depression: guilt by association

Neuroscientist. 2004 Dec;10(6):575-93. doi: 10.1177/1073858404267382.


The serotonin system is implicated in major depression and suicide and is negatively regulated by somatodendritic 5-HT1A autoreceptors. Desensitization of 5-HT1A autoreceptors is implicated in the 2- to 3-week latency for antidepressant treatments. Alterations in 5-HT1A receptor levels are reported in depression and suicide, and gene knockout of the 5-HT1A receptor results in an anxiety phenotype, suggesting that abnormal transcriptional regulation of this receptor gene may underlie these disorders. The 5-HT1A receptor gene is negatively regulated in neurons by repressors including REST/NRSF, Freud-1, NUDR/Deaf-1, and Hes5. The association with major depression, suicide, and panic disorder of a new functional 5-HT1A polymorphism at C(-1019)G that selectively blocks repression of the 5-HT1A autoreceptor by NUDR further suggests a causative role for altered regulation of this receptor in predisposition to mental illness. The authors review evidence that altered transcription of the 5-HT1A receptor can affect the serotonin system and limbic and cortical areas, leading to predisposition to depression.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / physiopathology
  • Depressive Disorder, Major / genetics*
  • Depressive Disorder, Major / metabolism
  • Depressive Disorder, Major / physiopathology
  • Disease Models, Animal
  • Genes, Regulator / genetics
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Mutation / genetics
  • Receptor, Serotonin, 5-HT1A / genetics*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Serotonin / metabolism


  • Repressor Proteins
  • Receptor, Serotonin, 5-HT1A
  • Serotonin