RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis.

A Ferrés-Coy,V Paz,A Montefeltro,A Bortolozzi,Á Pazos,L Campa,E M Valdizán,F Artigas,R Vidal,F Pilar-Cuellar,R Cortés,M Masana,M C Carmona

doi:10.1038/tp.2012.135

Abstract

Current antidepressants, which inhibit the serotonin transporter (SERT), display limited efficacy and slow onset of action. Here, we show that partial reduction of SERT expression by small interference RNA (SERT-siRNA) decreased immobility in the tail suspension test, displaying an antidepressant potential. Moreover, short-term SERT-siRNA treatment modified mouse brain variables considered to be key markers of antidepressant action: reduced expression and function of 5-HT1A-autoreceptors, elevated extracellular serotonin in forebrain and increased neurogenesis and expression of plasticity-related genes (BDNF, VEGF, Arc) in hippocampus. Remarkably, these effects occurred much earlier and were of greater magnitude than those evoked by long-term fluoxetine treatment. These findings highlight the critical role of SERT in serotonergic function and show that the reduction of SERT expression regulates serotonergic neurotransmission more potently than pharmacological blockade of SERT. The use of siRNA-targeting genes in serotonin neurons (SERT, 5-HT1A-autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants.

Highlights

Despite the high prevalence of depression and its considerable socioeconomic impact, its pathophysiological mechanisms remain poorly understood.[1,2,3] Serotonin (5-HT) participates in the etiology and treatment of major depression, being the selective serotonin reuptake inhibitors (SSRIs), the most common antidepressant therapy
Histological analysis revealed a significant decrease of serotonin transporter (SERT) expression in dorsal raphe nucleus (DR)—but not in median raphe nucleus (MnR)—of SERT-small interference RNA (siRNA)-treated mice (SERT mRNA and binding levels were 63±4% and 70±8%, respectively versus vehicle and ns-siRNA-treated mice)
The present study shows that partial RNA interference (RNAi)-based reduction of SERT expression in mouse DR has dramatic effects on serotonergic neurotransmission

Summary

Introduction

Despite the high prevalence of depression and its considerable socioeconomic impact, its pathophysiological mechanisms remain poorly understood.[1,2,3] Serotonin (5-HT) participates in the etiology and treatment of major depression, being the selective serotonin reuptake inhibitors (SSRIs), the most common antidepressant therapy. SERT is localized to raphe 5HT neurons at somatodendritic and terminal levels.[7,8,9] SERT blockade by SSRIs (showing nM affinity for SERT)[10] initiates the chain of events leading eventually to clinical improvement. Long-term SSRI treatment promotes an internalization of SERT from the cell surface in 5-HT neurons without affecting SERT mRNA expression.[11,12,13,14,15] In addition to loss of 5-HT1Aautoreceptor function,[16,17,18] SERT down-regulation may enhance forebrain 5-HT neurotransmission contributing to the therapeutic action of SSRIs.[19,20]

Methods

Results

Conclusion