title: Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator.
abstract: 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.
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Han
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Allen
authors.forename: Christie M
authors.initials: CM
authors.lastname: Buchovecky
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Yetman
authors.forename: Heather A
authors.initials: HA
authors.lastname: Born
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Marin
authors.forename: Shaefali P
authors.initials: SP
authors.lastname: Rodgers
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Song
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Lu
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Probst
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Jankowsky
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002874:Chromosome Mapping; D003213:Conditioning, Psychological / Q000502:physiology; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D008297:Male; D018782:Maze Learning / Q000502:physiology; D001523:Mental Disorders / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020258:Neurotoxicity Syndromes / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D013045:Species Specificity; D013752:Tetracycline / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D000900:Anti-Bacterial Agents; C078201:Aplp1 protein, mouse; D015534:Trans-Activators; D016875:tau Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D013752:Tetracycline; D004318:Doxycycline