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

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 po...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566716/
https://www.ncbi.nlm.nih.gov/pubmed/23321808
http://dx.doi.org/10.1038/tp.2012.135
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author 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
author_facet 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
author_sort Ferrés-Coy, A
collection PubMed
description 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.
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spelling pubmed-35667162013-02-08 RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis 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 Transl Psychiatry Original Article 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. Nature Publishing Group 2013-01 2013-01-15 /pmc/articles/PMC3566716/ /pubmed/23321808 http://dx.doi.org/10.1038/tp.2012.135 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
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
RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis
title RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis
title_full RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis
title_fullStr RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis
title_full_unstemmed RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis
title_short RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis
title_sort rnai-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566716/
https://www.ncbi.nlm.nih.gov/pubmed/23321808
http://dx.doi.org/10.1038/tp.2012.135
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