Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans

Here, we report generation and characterization of Disrupted-In-Schizophrenia-1 (DISC1) genetically engineered mice as a potential model for major mental illnesses, such as schizophrenia. DISC1 is a promising genetic risk factor for major mental illnesses. In this transgenic model, a dominant-negati...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 104; no. 36; pp. 14501 - 14506
Main Authors Hikida, Takatoshi, Jaaro-Peled, Hanna, Seshadri, Saurav, Oishi, Kenichi, Hookway, Caroline, Kong, Stephanie, Wu, Di, Xue, Rong, Andradé, Manuella, Tankou, Stephanie, Mori, Susumu, Gallagher, Michela, Ishizuka, Koko, Pletnikov, Mikhail, Kida, Satoshi, Sawa, Akira
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 04.09.2007
National Acad Sciences
SeriesFrom the Cover
Subjects
Animals
Behavior modeling
Behavior, Animal
Biological Sciences
Biomarkers
Disease models
Disease Models, Animal
Genes, Dominant - genetics
Genetics
Genotype & phenotype
Hippocampus
Human genetics
Humans
Lateral ventricles
Medical genetics
Mental illness
Mice
Mice, Transgenic
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurons
Phenotype
Rodents
Schizophrenia
Schizophrenia - diagnosis
Schizophrenia - genetics
Schizophrenia - physiopathology
Transgenic animals
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Summary:Here, we report generation and characterization of Disrupted-In-Schizophrenia-1 (DISC1) genetically engineered mice as a potential model for major mental illnesses, such as schizophrenia. DISC1 is a promising genetic risk factor for major mental illnesses. In this transgenic model, a dominant-negative form of DISC1 (DN-DISC1) is expressed under the αCaMKII promoter. In vivo MRI of the DN-DISC1 mice detected enlarged lateral ventricles particularly on the left side, suggesting a link to the asymmetrical change in anatomy found in brains of patients with schizophrenia. Furthermore, selective reduction in the immunoreactivity of parvalbumin in the cortex, a marker for an interneuron deficit that may underlie cortical asynchrony, is observed in the DN-DISC1 mice. These results suggest that these transgenic mice may be used as a model for schizophrenia. DN-DISC1 mice also display several behavioral abnormalities, including hyperactivity, disturbance in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit.
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Author contributions: T.H. and H.J.-P. contributed equally to this work; T.H., H.J.-P., and A.S. designed research; T.H., H.J.-P., S.S., C.H., S. Kong, R.X., M.A., and S.T. performed research; S.M., M.G., M.P., and S. Kida contributed new reagents/analytic tools; T.H., H.J.-P., K.O., D.W., and K.I. analyzed data; and T.H., H.J.-P., and A.S. wrote the paper.
Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 5, 2007
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0704774104