miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants

Science. 2010 Sep 17;329(5998):1537-41. doi: 10.1126/science.1193692.

Abstract

The serotonin transporter (SERT) ensures the recapture of serotonin and is the pharmacological target of selective serotonin reuptake inhibitor (SSRI) antidepressants. We show that SERT is a target of microRNA-16 (miR-16). miR-16 is expressed at higher levels in noradrenergic than in serotonergic cells; its reduction in noradrenergic neurons causes de novo SERT expression. In mice, chronic treatment with the SSRI fluoxetine (Prozac) increases miR-16 levels in serotonergic raphe nuclei, which reduces SERT expression. Further, raphe exposed to fluoxetine release the neurotrophic factor S100β, which acts on noradrenergic cells of the locus coeruleus. By decreasing miR-16, S100β turns on the expression of serotonergic functions in noradrenergic neurons. Based on pharmacological and behavioral data, we propose that miR-16 contributes to the therapeutic action of SSRI antidepressants in monoaminergic neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Antidepressive Agents, Second-Generation / administration & dosage
  • Antidepressive Agents, Second-Generation / metabolism
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Cell Line
  • Depression
  • Fluoxetine / administration & dosage
  • Fluoxetine / metabolism
  • Fluoxetine / pharmacology*
  • HeLa Cells
  • Humans
  • Locus Coeruleus / metabolism
  • Mice
  • MicroRNAs / administration & dosage
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Nerve Growth Factors / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Norepinephrine / metabolism
  • Protein Biosynthesis
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / metabolism*
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins / metabolism
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / metabolism
  • Serotonin Uptake Inhibitors / pharmacology*
  • Up-Regulation

Substances

  • 3' Untranslated Regions
  • Antidepressive Agents, Second-Generation
  • MicroRNAs
  • Mirn16 microRNA, mouse
  • Nerve Growth Factors
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a4 protein, mouse
  • Fluoxetine
  • Serotonin
  • Norepinephrine