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

• Published in: Translational psychiatry 2011-11, Vol.1 (11), p.e56-e56
• Main Authors: Launay, J M, Mouillet-Richard, S, Baudry, A, Pietri, M, Kellermann, O
• Format: Article
• Language: English
• Subjects: 631/136/368; 631/337/384/331; 692/699/476/1414; 692/700/565/1436; Adult; Animals; Behavior, Animal - drug effects; Behavior, Animal - physiology; Behavioral Sciences; Biological Psychology; 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; Medicine; Medicine & Public Health; Mice; MicroRNAs - physiology; Neurosciences; Original; original-article; Pharmacotherapy; Psychiatry; Raphe Nuclei - drug effects; Raphe Nuclei - physiology; Raphe Nuclei - surgery; Selective Serotonin Reuptake Inhibitors - administration & dosage; Signal Transduction - genetics
• ISSN: 2158-3188; 2158-3188
• 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.