Major depressive disorder (MDD) is a severe psychiatric syndrome with very-high socioeconomic impact worldwide (Global Burden of Disease Study 2013 Collaborators, 2015). This is attributable to three main factors: (i) MDD is a highly prevalent disorder in the general population, (ii) depressive episodes have long duration and occur during active periods of adult life, resulting in very large labor costs, and (iii) standard MDD treatments have limited efficacy, leaving a high percentage of patients with incomplete responses and poor quality of life, thus increasing suicide risk (Rush et al, 2006).

On the basis of clinical and preclinical studies, MDD may be associated with altered structural and synaptic plasticity, stress- or immune-related pathology, and genetic polymorphisms in brain circuits regulating mood and cognition (Ota and Duman, 2013). In this context, RNA interference (RNAi) may be a useful tool to examine the role of candidate genes in the pathophysiology and treatment of MDD. Hence, RNAi can be used as a therapeutic tool to silence targets involved in the disease process. However, despite its enormous potential, in vivo use of RNAi is limited due to the difficulty to deliver sequences of small RNAs (small interfering RNA-siRNA) to the desired neurons/circuits in mammalian brain. Our strategy has been to develop conjugate siRNA molecules (C-siRNA) in which the siRNA sequence was covalently bound to a selective serotonin reuptake inhibitor (SSRI-sertraline) in order to selectively accumulate it by the dense network of serotonin axon terminals in brain. The amounts (typically 0.5–2 nmol/day) of C-siRNA directed against 5-HT1A receptors (5-HT1A-R) or the serotonin transporter (SERT) were then administered intranasally to mice and C-siRNA sequences were localized into raphe serotonin neurons (Bortolozzi et al, 2012; Ferrés-Coy et al, 2016). Using this strategy, we discerned the role of pre- and postsynaptic 5-HT1A-R in response to stress, anxiety phenotype, and response to antidepressant treatments. Interestingly, the selective silencing of presynaptic 5-HT1A autoreceptors was sufficient to elicit antidepressant-like effects in mice thanks to the increased capability of serotonergic neurons to release serotonin during stressful situations (Bortolozzi et al, 2012; Ferrés-Coy et al, 2013).

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