tetracycline and Mental-Disorders

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.

Topics: Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Anti-Bacterial Agents; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Chromosome Mapping; Conditioning, Psychological; Dentate Gyrus; Disease Models, Animal; Doxycycline; Exploratory Behavior; Fear; Female; Male; Maze Learning; Mental Disorders; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Mutation; Neurotoxicity Syndromes; Species Specificity; tau Proteins; Tetracycline; Trans-Activators

We created the Flexible Accelerated STOP Tetracycline Operator (tetO)-knockin (FAST) system, an efficient method for manipulating gene expression in vivo to rapidly screen animal models of disease. A single gene targeting event yields two distinct knockin mice-STOP-tetO and tetO knockin-that permit generation of multiple strains with variable expression patterns: 1) knockout, 2) Cre-mediated rescue, 3) tetracycline-controlled transcriptional activator (tTA)-mediated misexpression, 4) tetracycline-controlled transcriptional activator (tTA)-mediated overexpression, and 5) tetracycline-controlled transcriptional silencer (tTS)-mediated conditional knockout/knockdown. Using the FAST system, multiple gain-of-function and loss-of-function strains can therefore be generated on a time scale not previously achievable. These strains can then be screened for clinically relevant abnormalities. We demonstrate the flexibility and broad applicability of the FAST system by targeting several genes encoding proteins implicated in neuropsychiatric disorders: Mlc1, neuroligin 3, the serotonin 1A receptor, and the serotonin 1B receptor.

Topics: Animals; Animals, Genetically Modified; Astrocytes; Bacterial Proteins; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carrier Proteins; Cell Line; Gene Expression; Gene Silencing; Gene Transfer Techniques; Mental Disorders; Mice; Mice, Knockout; Nervous System Diseases; RNA, Messenger; Tetracycline

Topics: Adult; Asthenia; Brucella abortus; Brucellosis; Depression; Fever; Humans; Male; Mental Disorders; Serologic Tests; Tetracycline

Topics: Adolescent; Adult; Bites and Stings; Blood Cell Count; Blood Coagulation Tests; Child; Child, Preschool; Chloramphenicol; Complement Fixation Tests; Female; Fever; Headache; Humans; Leukocytosis; Male; Mental Disorders; Rocky Mountain Spotted Fever; Seasons; Serologic Tests; Skin Diseases; South Carolina; Tetracycline; Ticks

Topics: Humans; Kidney Failure, Chronic; Mental Disorders; Tetracycline

Topics: Adult; Biguanides; Female; Humans; Male; Mental Disorders; Middle Aged; Nervous System Diseases; Tetracycline

Topics: Anti-Bacterial Agents; Chloramphenicol; Communicable Disease Control; Dysentery, Bacillary; Furazolidone; Kanamycin; Mental Disorders; Morbidity; Oxytetracycline; Paromomycin; Persons with Mental Disabilities; Protein Synthesis Inhibitors; Quinidine; Shigella dysenteriae; Sulfathiazoles; Tetracycline

Topics: Anti-Bacterial Agents; Humans; Lupus Erythematosus, Systemic; Mental Disorders; Tetracycline

Topics: Aged; Anti-Bacterial Agents; Antibiotics, Antitubercular; Dementia; Humans; Mental Disorders; Mentally Ill Persons; Oxytetracycline; Psychotic Disorders; Tetracycline