Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Abstract

The etiology of major depression remains unclear, but reduced activity of the serotonin (5-HT) system remains implicated and treatments that increase 5-HT neurotransmission can ameliorate depressive symptoms. 5-HT1A receptors are critical regulators of the 5-HT system. They are expressed as both presynaptic autoreceptors that negatively regulate 5-HT neurons, and as postsynaptic heteroreceptors on non-serotonergic neurons in the hippocampus, cortex, and limbic system that are critical to mediate the antidepressant actions of 5-HT. Thus, 5-HT1A auto-and heteroreceptors have opposite actions on serotonergic neurotransmission. Because most 5-HT1A ligands target both auto-and heteroreceptors their efficacy has been limited, resulting in weak or unclear responses. We propose that by understanding the transcriptional regulation of the 5-HT1A receptor it may be possible to regulate its expression differentially in raphe and projection regions. Here we review the transcriptional architecture of the 5-HT1A gene (HTR1A) with a focus on specific DNA elements and transcription factors that have been shown to regulate 5-HT1A receptor expression in the brain. Association studies with the functional HTR1A promoter polymorphism rs6295 suggest a new model for the role of the 5-HT1A receptor in susceptibility to depression involving early deficits in cognitive, fear and stress reactivity as stressors that may ultimately lead to depression. We present evidence that by targeting specific transcription factors it may be possible to oppositely regulate 5-HT1A auto-and heteroreceptor expression, synergistically increasing serotonergic neurotransmission for the treatment of depression. KeywordsSerotonin; repressor; enhancer; antidepressant; raphe; autoreceptor SEROTONIN AND MAJOR DEPRESSIONDepression continues to grow as a major health challenge with a lifetime prevalence for major depressive disorder (MDD) estimated at 16 % [1, 2] (Box 1). In developed countries, MDD currently accounts for the second highest lifetime burden of disease, and is predicted

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Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior

“…The HTR1A gene contains a series of repressor elements upstream of the promoter that suppress its expression (Albert and Fiori, 2014). Within the repressor region, a strong dual repressor element (DRE) binds to Freud-1/Cc2d1a, which represses HTR1A transcription in neuronal and non-neuronal cells (Ou et al, 2000;Ou et al, 2003;Lemonde et al, 2004a;.…”

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].…”