Journal
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
Volume 367, Issue 1601, Pages 2402-2415Publisher
ROYAL SOC
DOI: 10.1098/rstb.2011.0376
Keywords
serotonin; transcription; receptor; raphe; anxiety; depression
Categories
Funding
- Canadian Institutes of Health Research
- Heart and Stroke Centre for Stroke Recovery
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The serotonin-1A (5-HT1A) 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-HT1A receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT1A 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-HT1A 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-HT1A autoreceptor expression in animal models and humans. Its association with altered 5-HT1A 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 x environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT1A heteroreceptors, and rs6295-induced upregulation of 5-HT1A autoreceptors. Targeted therapeutics to inhibit 5-HT1A autoreceptor expression and induce 5-HT1A heteroreceptor expression may ameliorate treatment of anxiety and major depression.
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