Selective Knockdown of TASK3 Potassium Channel in Monoamine Neurons: a New Therapeutic Approach for Depression.
M Neus FullanaAlbert Ferrés-CoyJorge E OrtegaEsther Ruiz-BronchalVerónica PazJ Javier MeanaFrancesc ArtigasAnalia BortolozziPublished in: Molecular neurobiology (2018)
Current pharmacological treatments for major depressive disorder (MDD) are severely compromised by both slow action and limited efficacy. RNAi strategies have been used to evoke antidepressant-like effects faster than classical drugs. Using small interfering RNA (siRNA), we herein show that TASK3 potassium channel knockdown in monoamine neurons induces antidepressant-like responses in mice. TASK3-siRNAs were conjugated to cell-specific ligands, sertraline (Ser) or reboxetine (Reb), to promote their selective accumulation in serotonin (5-HT) and norepinephrine (NE) neurons, respectively, after intranasal delivery. Following neuronal internalization of conjugated TASK3-siRNAs, reduced TASK3 mRNA and protein levels were found in the brainstem 5-HT and NE cell groups. Moreover, Ser-TASK3-siRNA induced robust antidepressant-like behaviors, enhanced the hippocampal plasticity, and potentiated the fluoxetine-induced increase on extracellular 5-HT. Similar responses, yet of lower magnitude, were detected for Reb-TASK3-siRNA. These findings provide substantial support for TASK3 as a potential target, and RNAi-based strategies as a novel therapeutic approach to treat MDD.
Keyphrases
- major depressive disorder
- bipolar disorder
- spinal cord
- high glucose
- cancer therapy
- single cell
- diabetic rats
- cell therapy
- photodynamic therapy
- drug induced
- depressive symptoms
- binding protein
- oxidative stress
- type diabetes
- cerebral ischemia
- brain injury
- insulin resistance
- drug delivery
- sleep quality
- endothelial cells
- high fat diet induced
- bone marrow
- small molecule
- subarachnoid hemorrhage
- blood brain barrier