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 post-synaptic 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.
Keywords: Serotonin, repressor, enhancer, antidepressant, raphe, autoreceptor.
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