MicroRNA in the regulation and expression of serotonergic transmission in the brain and other tissues.

In addition to transcriptional regulation, the translation of protein-coding genes is modulated by MicroRNA-binding miRNAs (miRNAs), which have emerged to fulfil important roles in the control and expression of serotonergic transmission. Thus, miR-96 and miR-510 inhibit the translation of serotonin (5-HT)(1B) receptors and 5-HT(3E) receptor subunits respectively, and their susceptibility to repression is modified by polymorphisms in the 3'-UTR (miRNA-binding) regions of their mRNAs. Contrasting susceptibility of human subjects to miRNA-induced alterations in the translation of cerebral 5-HT(1B) receptors and intestinal 5-HT(3E) receptor subunits is related to differential aggressive behaviour and incidence of irritable bowel syndrome, respectively. Fluoxetine promotes the biogenesis of miR-16, leading to translational repression of 5-HT transporters in mouse serotonergic neurones. While the precise mechanism of action of fluoxetine is uncertain, studies of Aplysia have shown that 5-HT inhibits the generation of miR-124, thereby promoting de-repression of CREB and facilitation of synaptic plasticity. Interestingly, 5-HT(2C) receptors harbour a miRNA (miR-448) in their 4th intron that - oppositely to 5-HT(2C) sites - reduces adipocyte differentiation. Finally, interactions amongst 5-HT and miRNAs control processes of bone formation, as well as growth, motility and survival of tumours. The present article discusses the functionally and clinically important interplay amongst miRNAs and serotoninergic mechanisms in the brain, peripheral organs and cancerous tissue.