Global down-regulation of gene expression in the brain using RNA interference, with emphasis on monoamine transporters and GPCRs: implications for target characterization in psychiatric and neurological disorders.
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Hoyer, Daniel, Thakker, Deepak, Natt, Francois, Maier, Rainer, Huesken, Dieter, Mueller, Matthias, Flor, Peter Josef, Van Der Putten, P. Herman, Schmutz, Markus, Bilbe, Graeme and Cryan, John F. (2006) Global down-regulation of gene expression in the brain using RNA interference, with emphasis on monoamine transporters and GPCRs: implications for target characterization in psychiatric and neurological disorders. Journal of Receptor and Signal Transduction Research, 26 (5-6). pp. 527-547. ISSN 1079-9893
Abstract
RNA interference (RNAi) is a natural mechanism for regulating gene expression, which exists in plants, invertebrates, and mammals. We investigated whether non-viral infusion of short interfering RNA (siRNA) by the intracerebroventricular route would enable a sequence-specific gene knockdown in the mouse brain and whether the knockdown translates into disease-relevant behavioral changes. Initially, we targeted enhanced green fluorescent protein (EGFP) in mice overexpressing EGFP. A selective knockdown of both EGFP protein and mRNA was observed throughout the brain, with lesser down-regulation in regions distal to the infusion site. We then targeted endogenous genes, encoding the dopamine (DAT) and serotonin transporters (SERT). DAT-siRNA infusion in adult mice produced a significant down-regulation of DAT mRNA and protein and elicited hyperlocomotion similar, but delayed, to that produced on infusion of GBR-12909, a potent and selective DAT inhibitor. Similarly, SERT-siRNA infusion resulted in significant knockdown of SERT mRNA and protein and elicited reduced immobility in the forced swim test similar to that obtained on infusion of citalopram, a very selective and potent SSRI. Application of this non-viral RNAi approach may accelerate target validation for neuropsychiatric disorders that involve a complex interplay of gene(s) from various brain regions.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); 12 month embargo for STM Journals ; 18 month embargo for SSH journals; Publisher's version/PDF cannot be used; Must link to publisher version |
| Keywords: | RNAinterference; Anxiety; Depression; Forced swim test; Locomotor activity; GBR12099; Citalopram; In vivo; Dopamine and serotonin transporters |
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| Date Deposited: | 14 Dec 2009 13:57 |
| Last Modified: | 31 Jan 2013 01:13 |
| URI: | https://oak.novartis.com/id/eprint/566 |