title: Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function.
abstract: We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a microRNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in long-term potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient microRNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.
authors.affiliation: Brain Research Institute, University of Zürich and Department of Health Sciences and Technology, Eidgenössiche Technische Hochschule, Switzerland, 8057 Zürich, Switzerland.
authors.forename: Björn
authors.initials: B
authors.lastname: Tews
authors.forename: Kai
authors.initials: K
authors.lastname: Schönig
authors.forename: Michael E
authors.initials: ME
authors.lastname: Arzt
authors.forename: Stefano
authors.initials: S
authors.lastname: Clementi
authors.forename: Mengia-Seraina
authors.initials: MS
authors.lastname: Rioult-Pedotti
authors.forename: Ajmal
authors.initials: A
authors.lastname: Zemmar
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Berger
authors.forename: Miriam
authors.initials: M
authors.lastname: Schneider
authors.forename: Thomas
authors.initials: T
authors.lastname: Enkel
authors.forename: Oliver
authors.initials: O
authors.lastname: Weinmann
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Kasper
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
authors.forename: Dusan
authors.initials: D
authors.lastname: Bartsch
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology; D035683:MicroRNAs / Q000494:pharmacology*; D009185:Myelin Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D000070798:Nogo Proteins; D034622:RNA Interference; D051381:Rats; D055647:Rats, Transgenic; D013569:Synapses / Q000502:physiology*; D019076:Transgenes / Q000235:genetics
chemical_list: D035683:MicroRNAs; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603197:Rtn4 protein, rat; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins