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Antidepressant effects of RNAi strategies: focus on 5-HT genes

AutorArtigas, Francesc
Fecha de publicación21-jun-2014
CitaciónCCNP 37th Annual Meeting (2014)
ResumenMajor depression is a high-prevalence disease lacking appropriate treatment. SSRIs and SNRIs show delayed and limited clinical action, leaving a large proportion of patients with recurrent or chronic depression. 5-HT1A autoreceptors largely contribute to this scenario by preventing adequate responses of 5-HT neurons to stress. Moreover, the indirect activation of 5-HT1A autoreceptors by SSRIs and SNRIs limits their clinical effects. Recently, we examined the validity of RNA interference (RNAi) strategies to evoke antidepressant-like responses in rodents. The intra-dorsal raphe (DR) application of small interfering RNA (siRNA) targeting 5-HT1A autoreceptors selectively reduced their expression and function and evoked antidepressant-like responses in mice. Similarly, the intra-DR application of a siRNA targeting the 5-HT transporter modified mouse brain variables considered to be key markers of antidepressant action: enhanced forebrain 5-HT function, increased hippocampal neurogenesis and increased expression of plasticity-related genes. A major limitation of RNAi strategies is the difficulty to deliver oligonucleotides to selected brain neurons/systems. We developed a conjugated siRNA targeting 5-HT1A autoreceptors, covalently bound to the SSRI sertraline, for its selective delivery to 5-HT neurons after i.c.v. or intranasal administration. Short-term administration of this conjugated siRNA by both routes reduced the expression and function of 5-HT1A autoreceptors and evoked robust antidepressant-like responses in mice. We are currently exploring novel targets linked to monoamine function such as the TASK3 K+ channel, which controls neuronal excitability, also with promising results. Overall these data suggest that siRNA-based strategies targeting 5-HT-related genes may have an important therapeutic potential in the treatment of major depression
DescripciónPonencia presentada en el CCNP 3rd Annual Meeting (Canadian College of Neuropsychopharmacology), celebrado del 18 al 21 de junio de 2014 en Banff, Alberta (Canadá)
URIhttp://hdl.handle.net/10261/128145
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