Transcriptional regulation at a HTR1A polymorphism associated with mental illness

Abstract

The serotonin-1A (5-HT1A) receptor serves as a hub to regulate the activity and actions of the serotonin system, and is expressed both as a presynaptic autoreceptor on raphe neurons, and as a major postsynaptic receptor in hippocampal, cortical, and hypothalamic regions involved in mood, emotion and stress response. As such, the level of expression of 5-HT1A receptors is implicated in the development of anxiety and depression phenotypes. This review focuses on the C(−1019)G (rs6295) promoter polymorphism of the 5-HT1A receptor gene (HTR1A) and its effect on the activity of transcription factors that recognize the C-allele, including Deaf-1, Hes1 and Hes5; its effects on 5-HT1A receptor expression in pre- and postsynaptic areas; as well as its implication in early postnatal development and adult neurogenesis in the hippocampus and cortex. Although several studies have now replicated the association of the G-allele with depression, panic disorder, neuroticism, and reduced response to antidepressant or antipsychotic treatment, ethnic, disease and genetic heterogeneity among subjects in different studies may obscure such associations. Gene–gene interaction studies suggest that the 5-HT1A receptor G(−1019) allele is a risk allele which could be used as a marker for depression and related mood disorders. Finally, association of the G(−1019) allele with increased raphe 5-HT1A binding potential, increased amygdala reactivity to emotional stimuli, and reduced amygdala volume, particularly in disease states, suggests a functional role for the C(−1019)G site in 5-HT1A receptor dys-regulation and predisposition to mental illness.

Introduction

Major depression is one of the most prevalent forms of mental illness, with a lifetime prevalence of 15% and is twice as frequent in women as in men (Doris et al., 1999, Fava and Kendler, 2000). The World Health Organization has predicted that by 2020 depression will have the second highest lifetime burden of disease (Lopez and Murray, 1998, WHO, 2001). However, our understanding of depression remains incomplete due to the limitations of clinical samples and the limited phenotypes of animal models (Cryan and Mombereau, 2004, Hasler et al., 2004). While recent findings have highlighted the potential importance of growth factors such as BDNF (brain-derived neurotrophic factor), neurogenesis, or additional neurotransmitter systems in depression (Altar, 1999, Berton and Nestler, 2006, Sahay and Hen, 2007), the strongest evidence remains for a key role of monoamine systems and particularly the serotonin system in the etiology and treatment of depression (Millan, 2004, Tremblay and Blier, 2006). Acute tryptophan depletion, which rapidly lowers brain serotonin levels, has been shown to trigger depression in remitted depressed patients, and induces depressed mood in normal subjects (Jans et al., 2007, Moore et al., 2000, Neumeister, 2003). The most effective antidepressant compounds target the monoamine systems, and SSRIs specifically target the serotonin system, augmenting serotonergic neurotransmission (Charney et al., 1990). In an effort to understand how dys-regulation of the serotonin system can lead to major depression the functional long polymorphic repeat in the promoter of the serotonin transporter, the 5-HTTLPR, was identified (Lesch et al., 1996). This polymorphism has been extensively studied and has been associated with depression (Hu et al., 2007, Serretti et al., 2007a), particularly in combination with life stress (Caspi et al., 2003, Kendler et al., 2005, Zalsman et al., 2006), and with response to antidepressant treatments. This polymorphism has recently been shown to affect 5-HTT expression in brain (Praschak-Rieder et al., 2007), although earlier studies found that 5-HTT levels are unaffected by the polymorphism (Lim et al., 2006, Parsey et al., 2006a, Shioe et al., 2003), suggesting that the polymorphism might not directly affect expression levels of the serotonin transporter or that compensatory regulation may occur. Therefore, the exact mechanisms underlying the association of 5-HTTLPR with depression remain unclear. These and many other studies have led to the concept that genetic polymorphisms that affect expression or function of key components in neurotransmitter or signaling systems can also affect predisposition to mental illness (Albert and Lemonde, 2004, Reif and Lesch, 2003).

We initially decided to examine the serotonin-1A (5-HT1A) receptor gene (HTR1A), based on several criteria that the gene:

• plays a key role in regulating the activity of the serotonin system;

• mediates serotonin actions on mood and emotion;

• encodes an antidepressant or anti-anxiety drug target; and

• has a simple genetic structure amenable for transcriptional analysis.

Assuming that alterations in the expression of the HTR1A gene would lead to predisposition or protection from major depression, we initially characterized transcriptional regulatory regions of this gene and the specific DNA elements and transcription factors that dictate its expression. We showed that the C(−1019)G polymorphism found in the regulatory region of the 5-HT1A promoter could affect the binding of nuclear proteins in an allele-specific manner, and therefore demonstrated that it was a new functional polymorphism (Albert et al., 1996, Albert and Lemonde, 2004).

Current evidence is presented in this review that suggests that this polymorphism, in combination with other genetic polymorphisms and environmental modulation, is associated with altered expression of 5-HT1A receptors and with depression and treatment response to SSRIs.