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In press. ; Current pharmacological treatments for major depressive disorder (MDD) are severely compromised by both slow action and limited efficacy. RNAi strategies have been used to evoke antidepressant-like effects faster than classical drugs. Using small interfering RNA (siRNA), we herein show that TASK3 potassium channel knockdown in monoamine neurons induces antidepressant-like responses in mice. TASK3-siRNAs were conjugated to cell-specific ligands, sertraline (Ser) or reboxetine (Reb), to promote their selective accumulation in serotonin (5-HT) and norepinephrine (NE) neurons, respectively, after intranasal delivery. Following neuronal internalization of conjugated TASK3-siRNAs, reduced TASK3 mRNA and protein levels were found in the brainstem 5-HT and NE cell groups. Moreover, Ser-TASK3-siRNA induced robust antidepressant-like behaviors, enhanced the hippocampal plasticity, and potentiated the fluoxetine-induced increase on extracellular 5-HT. Similar responses, yet of lower magnitude, were detected for Reb-TASK3-siRNA. These findings provide substantial support for TASK3 as a potential target, and RNAi-based strategies as a novel therapeutic approach to treat MDD. ; This work was supported by the following grants: SAF2015-68346-P (F.A.); SAF2013-48586-R (J.M.); SAF2016-75797-R (A.B.); Retos-Colaboración Subprograms RTC-2014-2812-1 and RTC-2015-3309-1 (A.B.); Ministry of Economy and Competitiveness (MINECO)—European Regional Development Fund (ERDF), UE; PI13/01390, Instituto de Salud Carlos III co-financed by ERDF (A.B.); IT616-13 Basque Government—ERDF (J.M.); 20003 NARSAD Independent Investigator (A.B.); and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). CERCA Programme/Generalitat de Catalunya is also acknowledged. M.N.F. and A.F-C. are recipients of a fellowship from the Spanish Ministry of Education, Culture and Sport. ; Peer reviewed

Open Access: This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.-- et al. ; 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. ; This research was supported by grants from Spanish Ministry of Science and Innovation-CDTI, with the participation of the DENDRIA Consortium; from Instituto de Salud Carlos III PI10/00290 and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM, P91C). Structural funds of the European Union, through the National Applied Research Projects (R+D+I 2008/11) and from the Catalan Government (grant 2009SGR220) are also acknowledged. ; Peer Reviewed

A Ferrés-Coy et al. ; Major depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs, mostly inhibiting the serotonin transporter (SERT). As a result, similar to 80% of patients show recurrent or chronic depression, resulting in a poor quality of life and increased suicide risk. RNA interference (RNAi) strategies have been preliminarily used to evoke antidepressant-like responses in experimental animals. However, the main limitation for the medical use of RNAi is the extreme difficulty to deliver oligonucleotides to selected neurons/systems in the mammalian brain. Here we show that the intranasal administration of a sertraline-conjugated small interfering RNA (C-SERT-siRNA) silenced SERT expression/function and evoked fast antidepressant-like responses in mice. After crossing the permeable olfactory epithelium, the sertraline-conjugated-siRNA was internalized and transported to serotonin cell bodies by deep Rab-7-associated endomembrane vesicles. Seven-day C-SERT-siRNA evoked similar or more marked responses than 28-day fluoxetine treatment. Hence, C-SERT-siRNA (i) downregulated 5-HT1A-autoreceptors and facilitated forebrain serotonin neurotransmission, (ii) accelerated the proliferation of neuronal precursors and (iii) increased hippocampal complexity and plasticity. Further, short-term C-SERT-siRNA reversed depressive -like behaviors in corticosterone-treated mice. The present results show the feasibility of evoking antidepressant -like responses by selectively targeting neuronal populations with appropriate siRNA strategies, opening a way for further translational studies. ; This work was supported by grants from CDTI—Spanish Ministry of Science and Innovation—DENDRIA contribution, 'nLife all rights reserved' (to AB and FA); Instituto de Salud Carlos III PI10/00290 and PI13/01390 (to AB), PI/10/0123 (to JCL) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM); NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation Grant 20003 (to AB); Ministry of Economy and Competitiveness SAF2012-35183 (to FA) and SAF2011-25020 (to AP); and Generalitat de Catalunya, Secretaria d'Universitat i Recerca del Departament d'Economia i Coneixement (SGR2014) Catalan Government Grant 2009SGR220 (to FA). Some of these grants are co-financed by the European Regional Development Fund 'A way to build Europe'. AF-C is a recipient of a fellowship from Spanish Ministry of Education, Culture and Sport. ; Peer Reviewed