Póster presentado en el 26th ECNP (European College of Neuropsychopharmacology) Congress, celebrado del 5 al 9 de octubre de 2013, en Barcelona (España) ; Abstract publicado en: European Neuropsychopharmacology 23(Suppl. 2): S313-S314 (2013). ISSN: 0924-977X. e-ISSN: 1873-7862. DOI: 10.1016/S0924-977X(13)70492-9 ; Despite extensive research, the neurobiology of major depressive disorder (MDD) remains poorly understood due to lack of biomarkers, relatively low rates of heritability, and heterogeneity of precipitating factors, including stress. Serotonin (5-HT) neurotransmitter is involved in the pathophysiology and treatment of MDD, being selective serotonin reuptake inhibitors (SSRIs) the most prescribed antidepressant drugs. However, SSRIs need to be administered for long time periods before clinical improvement emerges, and fully remit depressive symptoms in only one third of patients [1]. The serotonin transporter (SERT) is a key regulator of serotonergic neurotransmission, as it determinates the intensity and duration of 5-HT signaling at synapses. RNA interference (RNAi) is a potent and specific post-transcriptional mechanism to control brain gene expression. It also provides new strategies to modulate the brain function by introducing exogenous small interference RNA molecules (siRNA). Previously, we showed the feasibility of siRNAs to silence in vivo the 5-HT1A-autoreceptor expression in raphe 5-HT neurons [2,3]. Here, we used a multifaceted approach to assess the specificity and selectivity of partial SERT suppression in adult mice, following short-term SERT-siRNA treatment. We examined downstream changes on brain variables linked to antidepressant efficacy and compared SERT-siRNA effects with those of a standard SSRI (fluoxetine) treatment. Local infusion of SERT-siRNA molecules into dorsal raphe nucleus (DR) for 4-day (0.7 nmol/day) suppressed the SERT mRNA expression (63±4%). This was accompanied by a selective and widespread reduction of SERT-binding sites and protein levels by 30−40% in most brain regions analyzed. In agreement with this partial SERT suppression, a decreased SERT function was observed in SERT-siRNA treated mice. Moreover, a 4-day regimen with intra-DR SERT-siRNA modified brain variables considered to be key markers of antidepressant action, such as: a) down-regulated 5-HT1A-autoreceptor expression/function; b) augmented extracellular 5-HT concentration in DR-projecting areas including striatum and hippocampus; c) increased hippocampal neurogenesis (NeuroD-positive and DCX-positive cells to 129±5% and 137±9% of vehicle-treated mice, respectively) and, d) increased plasticity-associated gene expression (BDNF, VEGF and Arc) in different hippocampus subfields. In contrast, a 4-day regimen with fluoxetine (20 mg/kg/day, i.p.) did not alter any of these variables and only started to modify them after 15-day treatment. Finally, the intranasal administration of conjugated SERT-siRNA for 7-day (2.1 nmol/day), but not fluoxetine, reversed the behavioral dysfunction displayed by a depression mouse model related with the chronic corticosterone consumption: (a) reduced immobility time in the tail suspension test, (b) reduced latency to feed in the novelty suppressed feeding test without affecting the home food consumption and (c) increased sucrose consumption in the preference sucrose test. These findings highlight the critical role of SERT in the control of serotonergic function, including serotonin-mediated neural plasticity. They also support the use of siRNA targeting serotonergic genes (SERT, 5-HT1A-autoreceptor) as a new generation of antidepressant therapies with a potential greater efficacy faster onset of action than current treatments ; Peer Reviewed