Transcriptional regulation of the 5-HT_1Areceptor: 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.

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

“…Exposure to stressors modulates 5-HT1A levels in a variety of primate and non-primate species (Franklin et al, 2011;Jovanovic et al, 2011;Leventopoulos et al, 2009;Lopez et al, 1998;Spinelli et al, 2010;Wang et al, 2009). Also, in humans, 5-HT1A levels are impacted by a functional C(-1019)G single-nucleotide promoter polymorphism (SNP; rs6295) (Albert, 2012). The G-allele of this SNP impairs the binding of the repressor, Nuclear Deaf-1 Related factor (NUDR), in a raphe cell line.…”

The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms

“…The review of Albert [25] is a thorough update on recent discoveries in 5-HT 1A gene regulation, and its link with psychiatric disorders. It provides a strong argument that dysregulation of 5-HT 1A autoreceptor and heteroceptor (genetic or environmental in basis, or both) is a risk factor for depression and anxiety.…”

Escitalopram Response in Panic Disorder is Not Associated with Three 5-HT1A Receptor Gene Polymorphisms (Rs6295, Rs10042486, or Rs1364043) in Chinese-Han Patients

“…In addition, PD has been linked to increased cardiovascular morbidity and mortality, which typically increases the burden of suffering as well as economic costs [2,3]. Therefore, it is valuable to determine its etiology and provide targeted treatment methods for this disorder.…”

“…Thus, based on neuroimaging data, animal models, and genetic studies, the 5-HT1A receptor gene, located on chromosome 5 (5q11. [2][3][4][5][6][7][8][9][10][11][12][13], is a putative candidate gene for PD [7]. Of several gene polymorphisms, studies have focused on a functional C-1019G single nucleotide polymorphism (SNP rs6295) located in the promoter of HTR1A, which regulates HTR1A transcription, and is associated with schizophrenia, bipolar disorder, anxiety, depression-related personality traits, and antidepressant responses [8][9][10].…”