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

Ponencia presentada en el CCNP 3rd Annual Meeting (Canadian College of Neuropsychopharmacology), celebrado del 18 al 21 de junio de 2014 en Banff, Alberta (Canadá)Major 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 depressionPeer Reviewe