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

• Published in: Translational psychiatry 2013-01, Vol.3 (1), p.e211-e211
• Main Authors: Ferrés-Coy, A, Pilar-Cuellar, F, Vidal, R, Paz, V, Masana, M, Cortés, R, Carmona, M C, Campa, L, Pazos, Á, Montefeltro, A, Valdizán, E M, Artigas, F, Bortolozzi, A
• Format: Article
• Language: English
• Subjects: 631/154/51/391/505; 631/378/368; 631/378/548; 692/699/476/1414; Analysis of Variance; Animals; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Autoreceptors - genetics; Autoreceptors - metabolism; Behavioral Sciences; Biological Psychology; Brain-Derived Neurotrophic Factor - drug effects; Brain-Derived Neurotrophic Factor - genetics; Cytoskeletal Proteins - drug effects; Cytoskeletal Proteins - genetics; Fluoxetine - metabolism; Fluoxetine - pharmacology; Gene Expression; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Immunohistochemistry; In Situ Hybridization; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins - drug effects; Nerve Tissue Proteins - genetics; Neurogenesis - genetics; Neurogenesis - physiology; Neurosciences; Original; original-article; Pharmacotherapy; Psychiatry; Receptor, Serotonin, 5-HT1A - drug effects; Receptor, Serotonin, 5-HT1A - genetics; Receptor, Serotonin, 5-HT1A - metabolism; RNA Interference - physiology; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA, Small Interfering - pharmacology; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin Plasma Membrane Transport Proteins - pharmacology; Synaptic Transmission - drug effects; Synaptic Transmission - genetics; Vascular Endothelial Growth Factor A - drug effects; Vascular Endothelial Growth Factor A - genetics
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2012.135

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-HT 1A -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-HT 1A -autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants.