Unknown

Dataset Information

0

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


ABSTRACT: 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.

SUBMITTER: Ferres-Coy A 

PROVIDER: S-EPMC4759205 | BioStudies | 2016-01-01

SECONDARY ACCESSION(S): D50621

REPOSITORIES: biostudies

Similar Datasets

2013-01-01 | S-EPMC3566716 | BioStudies
2009-01-01 | S-EPMC2758934 | BioStudies
2012-01-01 | S-EPMC6622051 | BioStudies
2008-01-01 | S-EPMC2905844 | BioStudies
2012-01-01 | S-EPMC6072683 | BioStudies
2016-01-01 | S-EPMC4939133 | BioStudies
1000-01-01 | S-EPMC4540099 | BioStudies
2020-01-01 | S-EPMC7047617 | BioStudies
2019-01-01 | S-EPMC6445781 | BioStudies
2010-01-01 | S-EPMC2849739 | BioStudies