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Strain Background Influences Neurotoxicity and Behavioral Abnormalities in Mice Expressing the Tetracycline Transactivator
Open accessAbstract
The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer's, Parkinson's, Huntington's, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer's disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background and recurred on reintroduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds, indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.
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“The severity of these effects depends on the genetic background of the animal and possibly also on the (r)tTA version used.”
From Tet-On Systems For Doxycycline-inducible Gene Expression (2016) · cites this paper as [82]
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“In transgenic mice, toxic side-effects of tTA and rtTA have also been reported [79-83].”
From Tet-On Systems For Doxycycline-inducible Gene Expression (2016) · cites this paper as [82]
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Metadata
- Authors
- Han, H. J., Allen, C. C., Buchovecky, C. M., Yetman, M. J., Born, H. A., Marin, M. A., Rodgers, S. P., Song, B. J., Lu, H.-C., Justice, M. J., Probst, F. J., & Jankowsky, J. L.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Jankowsky, J. L.
- ORCID
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-08-01
- Volume
- 32
- Issue
- 31
- Pages
- 10574-10586
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3431916
- OpenAlex
- W2079978524
- Cited by
- 105
- References
- 60
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 22 · 2023: 9 · 2022: 8 · 2021: 9 · 2020: 6 · 2019: 10 · 2018: 7 · 2017: 9 · 2016: 7 · 2015: 6 · 2014: 4 · 2013: 3
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health (DP2OD001734, OD001734)
- National Institute on Aging (32-AG000183, K01AG026144, T32AG000183, AG026144)
- National Institute of General Medical Sciences (T32GM008307)
- National Institute of Neurological Disorders and Stroke (R01NS048884)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
- Keywords
- tetracycline transactivator, Tet-off system, neurodegeneration, dentate gyrus granule cells, spatial learning, contextual fear conditioning, genetic modifiers, chromosome 14, transgenic mouse model
- MeSH terms
- Analysis of Variance, Animals, Anti-Bacterial Agents, Mental Disorders, Chromosome Mapping, Conditioning, Psychological, Disease Models, Animal, Doxycycline, Exploratory Behavior, Fear, Female, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Species Specificity, Tetracycline, Trans-Activators, Amyloid beta-Protein Precursor, tau Proteins, Maze Learning, Dentate Gyrus, Neurotoxicity Syndromes, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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