5-HT1A receptors, gene repression, and depression: guilt by association.
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.
Albert
Paul R
PR
Ottawa Health Research Institute, Neuroscience University of Ottawa, Ottawa, Canada.
Lemonde
Sylvie
S
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005809:Genes, Regulator / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
D012097:Repressor Proteins; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin