MicroRNA-34a regulates 5-HT2C expression in dorsal raphe and contributes to the anti-depressant-like effect of fluoxetine

• Published in: Neuropharmacology 2021-06, Vol.190, p.108559-108559, Article 108559
• Main Authors: Lo Iacono, Luisa, Ielpo, Donald, Parisi, Chiara, Napoli, Giulia, Accoto, Alessandra, Di Segni, Matteo, Babicola, Lucy, D'Addario, Sebastian Luca, Guzzo, Serafina Manila, Pascucci, Tiziana, Ventura, Rossella, Andolina, Diego
• Format: Article
• Language: English
• Subjects: 5-HT2C; Animals; Antidepressive Agents, Second-Generation - pharmacology; Behavior, Animal - drug effects; Dorsal Raphe; Dorsal Raphe Nucleus - drug effects; Dorsal Raphe Nucleus - metabolism; Fluoxetine; Fluoxetine - pharmacology; Locomotion - drug effects; Locomotion - genetics; Mice; Mice, Knockout; MicroRNAs - drug effects; MicroRNAs - genetics; miR-34; RDoC; Receptor, Serotonin, 5-HT2C - drug effects; Receptor, Serotonin, 5-HT2C - genetics; Target Site Blocker; Up-Regulation
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2021.108559

Selective serotonin reuptake inhibitors (SSRIs) are designed to improve mood by raising extracellular serotonin levels through the blockade of the serotonin transporter. However, they exhibit a slow onset of action, suggesting the involvement of adaptive regulatory mechanisms. We hypothesized that the microRNA-34 family facilitates the therapeutic activity of SSRIs. We show that genetic deletion of these microRNAs in mice impairs the response to chronic, but not acute, fluoxetine treatment, with a specific effect on behavioral constructs that are related to depression, rather than anxiety. Moreover, using a pharmacological strategy, we found that an increased expression of the serotonin 2C (5-HT2C) receptor in the dorsal raphe region of the brain contributes to this phenotype. The onset of the therapeutic efficacy of SSRIs is paralleled by the desensitization of the 5-HT2C receptor in the dorsal raphe, and 5-HT2C is a putative target of microRNA-34. In this study, acute and chronic fluoxetine treatment differentially alters the expression of 5-HT2C and microRNA-34a in the dorsal raphe. Moreover, by in vitro luciferase assay, we demonstrated the repressive regulatory activity of microRNA-34a against 5-HT2C mRNA. Specific blockade of this interaction through local infusion of a target site blocker was sufficient to prevent the behavioral effects of chronic fluoxetine. Our results demonstrate a new miR-34a-mediated regulatory mechanism of 5-HT2C expression in the dorsal raphe and implicate it in eliciting the behavioral responses to chronic fluoxetine treatment. Molecular model of miR-34a/Htr2c regulation in the expression of fluoxetine antidepressant efficacy. In the Dorsal Raphe fluoxetine increases the level of extracellular 5-HT by inhibiting the 5-HT reuptake pump in serotoninergic neurons. The surge of extra-cellular 5-HT activates local gabaergic neurons by stimulating 5-HT2C receptors and up-regulating their transcription. This leads to an inhibition of 5-HT release that counteracts fluoxetine antidepressant activity. Under chronic administration fluoxetine up-regulates miR-34a, which, by targeting htr2c mRNA in gabaergic neurons, down-regulates the synthesis of 5-HT2C receptor. This feedback control on 5-HT2C receptors reduces the fluoxetine-induced gabaergic activation and allows the expression of the antidepressant fluoxetine activity. [Display omitted] •Acute and chronic fluoxetine in mice have opposite consequences on RDoC behavioral constructs r