title: RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis.
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-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.
authors: Department of Neurochemistry, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
authors: A
authors: A
authors: Ferrés-Coy
authors: F
authors: F
authors: Pilar-Cuellar
authors: R
authors: R
authors: Vidal
authors: V
authors: V
authors: Paz
authors: M
authors: M
authors: Masana
authors: R
authors: R
authors: Cortés
authors: M C
authors: MC
authors: Carmona
authors: L
authors: L
authors: Campa
authors: A
authors: A
authors: Pazos
authors: A
authors: A
authors: Montefeltro
authors: E M
authors: EM
authors: Valdizán
authors: F
authors: F
authors: Artigas
authors: A
authors: A
authors: Bortolozzi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology*; D017660:Autoreceptors / Q000235:genetics / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000235:genetics; D005473:Fluoxetine / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics* / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D017660:Autoreceptors; D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D050486:Serotonin Plasma Membrane Transport Proteins; D042461:Vascular Endothelial Growth Factor A; C092069:activity regulated cytoskeletal-associated protein; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A