Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

Abstract

The serotonin-1A (5-HT1A) receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A) using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019)G (rs6295) polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction

“…Furthermore, our experiments identified specific misregulated genes probably involved in these behavioural alterations. In particular, the changes in 5-HT1A receptor expression are considered an important determinant of predisposition to mental illness 33 and, although the mechanisms underlying the variable expression of this locus between individuals remain unclear, transcriptional dysregulation has been suggested as a probable candidate 34 . 5-HT2A and 5-HT1B receptors are also of great relevance for behavioural disorders 35,36 .…”

Transcriptional regulation of the 5-HT1Areceptor: implications for mental illness

“…To restrict Htr1a expression to neuronal cells, a series of repressor elements located upstream of the promoter coordinately silence the gene [73]. These include the RE-1 site for neural restrictive factor (REST/NRSF) [76] and a powerful dual repressor element that is regulated by a pair of conserved repressors, Freud-1/ CC2D1A and Freud-2/CC2D1B [77][78][79].…”

“…The Htr1a gene lacks introns in its coding region and is strongly expressed in specific brain regions, but almost not at all in non-neuronal tissues [69,70]. The Htr1a gene contains a GC-rich proximal promoter region containing DNA elements for several ubiquitous transcription factors, including Myc-associated zinc finger protein (MAZ), Sp1 and NFkB that drive its expression in all cell types examined [71][72][73]. By contrast, the Htr1a promoter also contains several Pet-1 sites recognized by the raphe-specific enhancer, Pet-1, which primarily enhances 5-HT 1A autoreceptor expression [74].…”

The Existence of FGFR1–5-HT1A Receptor Heterocomplexes in Midbrain 5-HT Neurons of the Rat: Relevance for Neuroplasticity

“…A dysregulation of the 5-HT1A autoreceptors leading to a marked reduction of the firing rate in the ascending raphe-forebrain 5-HT neurons has been implicated in major depression (Albert et al, 2011). It seems possible that a certain balance of activity at different postjunctional 5-HT receptor subtypes of the seven 5-HT receptor families identified (Hoyer et al, 2002) needs to be developed with time through adaptive changes to counteract the depression (Fuxe et al, 1991).…”