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

Luisa Lo Iacono, Donald Ielpo, Chiara Parisi, Giulia Napoli, Alessandra Accoto, Matteo Di Segni, Lucy Babicola, Sebastian Luca D'Addario, Serafina Manila Guzzo, Tiziana Pascucci, Rossella Ventura, Diego Andolina

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number108559
JournalNeuropharmacology
Volume190
DOIs
Publication statusPublished - Jun 1 2021

Keywords

  • 5-HT2C
  • Dorsal Raphe
  • Fluoxetine
  • miR-34
  • RDoC
  • Target Site Blocker

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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