Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16

Transl Psychiatry. 2011 Nov 22;1(11):e56. doi: 10.1038/tp.2011.54.


Serotonin reuptake inhibitor (SRI) antidepressants such as fluoxetine (Prozac), promote hippocampal neurogenesis. They also increase the levels of the bcl-2 protein, whose overexpression in transgenic mice enhances adult hippocampal neurogenesis. However, the mechanisms underlying SRI-mediated neurogenesis are unclear. Recently, we identified the microRNA miR-16 as an important effector of SRI antidepressant action in serotonergic raphe and noradrenergic locus coeruleus (LC). We show here that miR-16 mediates adult neurogenesis in the mouse hippocampus. Fluoxetine, acting on serotonergic raphe neurons, decreases the amount of miR-16 in the hippocampus, which in turn increases the levels of the serotonin transporter (SERT), the target of SRI, and that of bcl-2 and the number of cells positive for Doublecortin, a marker of neuronal maturation. Neutralization of miR-16 in the hippocampus further exerts an antidepressant-like effect in behavioral tests. The fluoxetine-induced hippocampal response is relayed, in part, by the neurotrophic factor S100β, secreted by raphe and acting via the LC. Fluoxetine-exposed serotonergic neurons also secrete brain-derived neurotrophic factor, Wnt2 and 15-Deoxy-delta12,14-prostaglandin J2. These molecules are unable to mimic on their own the action of fluoxetine and we show that they act synergistically to regulate miR-16 at the hippocampus. Of note, these signaling molecules are increased in the cerebrospinal fluid of depressed patients upon fluoxetine treatment. Thus, our results demonstrate that miR-16 mediates the action of fluoxetine by acting as a micromanager of hippocampal neurogenesis. They further clarify the signals and the pathways involved in the hippocampal response to fluoxetine, which may help refine therapeutic strategies to alleviate depressive disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / genetics*
  • Female
  • Fluoxetine / administration & dosage
  • Fluoxetine / pharmacology*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Humans
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism
  • Male
  • Mice
  • MicroRNAs / physiology*
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / physiology*
  • Raphe Nuclei / surgery
  • Selective Serotonin Reuptake Inhibitors / administration & dosage*
  • Signal Transduction / genetics*


  • MIRN16 microRNA, human
  • MicroRNAs
  • Serotonin Uptake Inhibitors
  • Fluoxetine