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.

Figure 1.

Model for Htr1a dysregulation in human anxiety and depression. Shown is a model of differential Htr1a regulation in pre-synaptic raphe 5-HT neurons projecting to post-synaptic neurons in target tissues involved in mood and affect, such as prefrontal cortex, hippocampus, amygdala or hypothalamus. Pre-synaptic 5-HT_1A autoreceptors (v) negatively regulate 5-HT firing neuronal activity and regulate the release of 5-HT (dots) and activation of post-synaptic 5-HT_1A heteroreceptors. In normal subjects, the set point for raphe firing frequency is determined in part by the density of 5-HT_1A autoreceptors that is restrained by repression at the rs6295 C(-1019) allele (bar); 5-HT_1A heteroreceptors, especially in cortex appear to be increased by enhancer activity at the C(-1019) allele (arrow). In anxiety, the combination of genetic (rs6295 G(-1019) allele) and environmental (life stress) glucocorticoid-mediated repression of the 5-HT_1A promoter leads to a stronger decrease in 5-HT_1A heteroreceptors in glucocorticoid-sensitive tissues, such as hippocampus and prefrontal cortex, and to a lesser extent the raphe nucleus; anxiety subjects appear to compensate for the de-repression of 5-HT_1A autoreceptors in the raphe. In depression, the combination of G(-1019) allele and stress promote reductions in post-synaptic 5-HT_1A heteroreceptors; however, pre-synaptic 5-HT_1A autoreceptors become upregulated due to the lack of Deaf1 repression at the G(-1019) allele, leading to reduced 5-HT release, and compensatory partial upregulation of 5-HT_1A heteroreceptors. In this model, antidepressants act mainly at heteroreceptors or other post-synaptic processes for anti-anxiety actions, while they also act to desensitize pre-synaptic sites to mediate antidepressant actions.