Selective knockdown of task3 potassium channels in monoaminergic neurons evokes antidepressant-like responses

Abstract

Depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs. Recently, two-pore domain K+ (K2P) TASK3 channel was described as a feasible target with antidepressant potential. TASK3 knockout mice displayed antidepressant-like behaviors. However, the mechanisms or brain regions involved in these responses are not clear. Here, we developed a siRNA against TASK3 conjugated with sertraline-S (serotonin-5-HT transporter inhibitor) or reboxetine-R (norepinephrine-NE transporter inhibitor) to examine whether knockdown of TASK3 channel in the dorsal raphe nucleus (DR) or locus coeruleus (LC), respectively, is sufficient to produce antidepressant-like effects. Firstly, we infused locally naked TASK3- -siRNA (10 ) or reboxetine-R (norepinephrine-NE transporter inhi±4% and 84±4% of control group, respectively). Intranasal administration (i.n) of Alexa488-labeled S-conjugated or R-conjugated-siRNA resulted in a selective enrichment of these molecules in 5-HT TPH2+ (DR) or NE TH+ (LC) neurons, but not in other brain regions. Moreover, short-term S-TASK3-siRNA treatment (7-day, i.n) reduced TASK3 mRNA density in TPH2+ neurons (intracelular density: 63±7% of control group), but not TREK1 and TASK1 channels nor 5-HT1A receptor and SERT. We found that DR TASK3 knockdown mice evoked antidepressantlike responses including: a) decreased immobility time in the tail suspension test, b) reduced 8-OHDPAT-induced 5-HT1A-autoreceptor function and, c) increased fluoxetine effect on extracellular 5-HT concentration in the medial prefrontal cortex. Our results suggest that TASK3 channel in monoaminergic neurons could be a potential target for treatments of depression disorders