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.
Highlights
Major depressive disorder (MDD) is a severe, chronic and lifethreatening disease with a high incidence; affecting ca. 120 million people worldwide.[1,2,3] The midbrain serotonin (5-hydroxytryptamine (5-HT)) system has a critical role in many brain functions, including mood control
A488C-NS-siRNA was absent in cells of brain areas close to the application site or to brain ventricles (Supplementary Figure S3), supporting that surface Serotonin transporter (SERT) expression is a requirement for oligonucleotide uptake and internalization
We show that C-SERT-siRNA evokes very fast (7-day) and robust antidepressant-like responses in control and corticosterone-treated mice, comparable than those evoked by a 28-day FLX treatment
Summary
Major depressive disorder (MDD) is a severe, chronic and lifethreatening disease with a high incidence; affecting ca. 120 million people worldwide.[1,2,3] The midbrain serotonin (5-hydroxytryptamine (5-HT)) system has a critical role in many brain functions, including mood control. Derangements of serotonin pathway are involved in MDD, and most antidepressant drugs aim to increase serotonergic function.[4] Serotonin transporter (SERT) is a key player in MDD, by controlling the active 5-HT fraction and, being the target of most prescribed antidepressant drugs, the selective serotonin reuptake inhibitors (SSRI) and the selective serotonin and norepinephrine reuptake inhibitors (SNRI).[5,6] These drugs need to be administered for long time before clinical improvement emerges, and they fully remit depressive symptoms in only onethird of patients leaving a large proportion of people with partial or incomplete clinical responses.[7,8] For these reasons, there is an urgent need to improve antidepressant treatments
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