Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function
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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.
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Nogo and NgR have been implicated in schizophrenia pathophysiology.
“Interestingly, Nogo and NgR have previously been implicated in the pathophysiology schizophrenia (Willi and Schwab, 2013)(Willi et al., 2010)(Tews et al., 2013)(Budel et al., 2008).”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Tews et al., 2013
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- Authors
- Tews, B., Schönig, K., Arzt, M. E., Clementi, S., Rioult-Pedotti, M.-S., Zemmar, A., Berger, S. M., Schneider, M., Enkel, T., Weinmann, O., Kasper, H., Schwab, M. E., & Bartsch, D.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University of Zurich (CH)
- Brown University (US)
- Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-04
- Volume
- 110
- Issue
- 16
- Pages
- 6583-6588
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3631667
- OpenAlex
- W2026883273
- Cited by
- 56
- References
- 62
- Citations by year
- 2025: 1 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 5 · 2018: 2 · 2017: 3 · 2016: 5 · 2015: 10 · 2014: 11 · 2013: 7
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (122527)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Nogo-A, synaptic plasticity, long-term potentiation, hippocampus, motor cortex, cognitive function, schizophrenia-like behavior, prepulse inhibition, perseveration, social withdrawal, oligodendrocytes, transgenic rats, RNA interference
- MeSH terms
- Nogo Proteins, Animals, Cognition, Gene Expression Regulation, Myelin Proteins, Neuronal Plasticity, Synapses, Long-Term Potentiation, Transgenes, RNA Interference, MicroRNAs, Green Fluorescent Proteins, Rats, Rats, Transgenic
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