title: Transcriptional regulation of the 5-HT1A receptor: implications for mental illness.
abstract: The serotonin-1A (5-HT(1A)) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre- and post-synaptic 5-HT(1A) receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT(1A) receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress-induced expression of the 5-HT(1A) receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT(1A) autoreceptor expression in animal models and humans. Its association with altered 5-HT(1A) expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene × environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT(1A) heteroreceptors, and rs6295-induced upregulation of 5-HT(1A) autoreceptors. Targeted therapeutics to inhibit 5-HT(1A) autoreceptor expression and induce 5-HT(1A) heteroreceptor expression may ameliorate treatment of anxiety and major depression.
authors: Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, , 451 Smyth Road, Ottawa, ON, Canada , K1H 8M5. palbert@uottawa.ca
authors: Paul R
authors: PR
authors: Albert
mesh_terms: D000483:Alleles; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017660:Autoreceptors / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D011401:Promoter Regions, Genetic; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000928:Antidepressive Agents; D017660:Autoreceptors; D014157:Transcription Factors; D044282:Receptor, Serotonin, 5-HT1A