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We thank Maria Calvo, Elisenda Coll and Anna Bosch for outstanding technical support in the Confocal microscopy unit (CCiT-UB) and Maria C Carmona for advice on design of small RNA and oligonucleotidc molecules. This work was supported by grants from CDTI-Spanish Ministry of Science and Innovation-DENDRIA contribution, 'nLife all rights reserved' (to AB and FA); Institute de Salud Carlos III PI10/00290 and PI13/01390 (to AB), PI/10/0123 (to JCL) and Centro de Investigation Biomedica 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 &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.

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Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration

Publicado en:Molecular Psychiatry. 21 (3): 328-338 - 2016-03-01 21(3), DOI: 10.1038/mp.2015.80

Autores: Ferres-Coy, A; Galofre, M; Pilar-Cuellar, F; Vidal, R; Paz, V; Ruiz-Bronchal, E; Campa, L; Pazos, A; Caso, J R; Leza, J C; Alvarado, G; Montefeltro, A; Valdizan, E M; Artigas, F; Bortolozzi, A

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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, ~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.

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