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.

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior

“…This suggests that HMGB1 is not required for hippocampal cytokine and chemokine increases induced by a single stress, which increased more rapidly, but HMGB1 may contribute to the priming effects of stress-pretreatment, leading to the accelerated rate of induction of most hippocampal cytokines and chemokines after two stresses. Since previously intranasal administration has been shown to allow modification of hippocampal functions and intranasal or intracerebroventricular administration of a variety of siRNA constructs have been shown to knockdown levels of proteins in the hippocampus (Bortolozzi et al, 2012; Kim et al, 2012; Ferres-Coy et al, 2013; Kanazawa et al, 2014; Ferres-Coy et al, 2015; Mohanty et al, 2015), we tested the effects of knocking down HMGB1 by intranasal siRNA administration, followed by measurements of hippocampal cytokines and chemokines that were increased at 3 hr after two stresses. Intranasal administration of HMGB1 siRNA eliminated the stress-induced increase in the hippocampal HMGB1 level at 3 hr after two stresses (one-way ANOVA; F (2, 12) = 9.957, p < 0.05: Figure 5B).…”

Regionally selective knockdown of astroglial glutamate transporters in infralimbic cortex induces a depressive phenotype in mice

“…All behavioral assessments were performed between 9:00 and 15:00 hr, 24 hr after the local microinfusion of aCSF or siRNA targeting GLAST or GLT‐1. Mice were evaluated in different behavioral paradigms: (a) open field test (OFT), (b) tail suspension test (TST), (c) forced swim test (FST) and, (d sucrose preference test (SPT) as previously reported (Bortolozzi et al, ; Ferrés‐Coy et al, ). On test day, animals were moved to a dimly illuminated room and were left undisturbed for at least 1 hr before testing.…”

Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion

“…Along these lines, in future experiments, it is important to determine when during the lifespan Mirta22 normalization is most effective at reversing behavioral and neurophysiological phenotypes and whether Mirta22 levels could be normalized by approaches as readily translatable into medical therapies as possible. These approaches include, for example, the application of siRNAs or shRNAs (73,74) or the use of antisense oligonucleotides to inhibit excessive Mirta22 gene expression based on their efficacy in preclinical models (75,76) and clinical studies (77,78) of neurodevelopmental or neurodegenerative disorders. Alternatively, use of genome editing via CRISPR could be another highly promising approach for modulating Mirta22 function (79,80).…”