title: Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16.
abstract: 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.
authors: AP-HP Service de Biochimie, Fondation FondaMental, Hôpital Lariboisière, Paris, France. jean-marie.launay@lrb.aphp.fr
authors: J M
authors: JM
authors: Launay
authors: S
authors: S
authors: Mouillet-Richard
authors: A
authors: A
authors: Baudry
authors: M
authors: M
authors: Pietri
authors: O
authors: O
authors: Kellermann
mesh_terms: D000328:Adult; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology* / Q000601:surgery; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D005473:Fluoxetine; D035683:MicroRNAs; D017367:Selective Serotonin Reuptake Inhibitors; C505362:MIRN16 microRNA, human