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

doi:10.1073/pnas.0704774104

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

Departments of *Psychiatry and Behavioral Sciences,
^†Radiology,
^§Neuroscience, and
^¶Psychology,
^‡Graduate Program in Cellular and Molecular Medicine, and
^‖Division of Neurobiology, The Johns Hopkins University, Baltimore, MD 21287; and
**Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 5, 2007 (received for review May 28, 2007)

Abstract

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.

Footnotes

^††To whom correspondence should be addressed. E-mail: asawa1{at}jhmi.edu
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.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0704774104/DC1.
Abbreviations:

DISC1,

Disrupted-In-Schizophrenia-1;

DN,

dominant-negative;

SZ,

schizophrenia;

wt,

wild-type;

tg,

transgenic.