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PNAS 100 (15): 8987-8992

Copyright © 2003 by the National Academy of Sciences.


Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia

Tsuyoshi Miyakawa*,{dagger}, Lorene M. Leiter*, David J. Gerber*, Raul R. Gainetdinov{ddagger}, Tatyana D. Sotnikova{ddagger}, Hongkui Zeng*,§, Marc G. Caron{ddagger}, and Susumu Tonegawa*

*Howard Hughes Medical Institute, The Picower Center for Learning and Memory and RIKEN/Massachusetts Institute of Technology Neuroscience Research Center, Departments of Biology and Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; and {ddagger}Howard Hughes Medical Institute, Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, NC 27710

Contributed by Susumu Tonegawa, May 15, 2003

Abstract: Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.

To whom correspondence should be addressed. E-mail: tonegawa{at}

{dagger} Present address: Horizontal Medical Research Organization, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan.

§ Present address: Primal Incorporated, 1124 Columbia Street, Seattle, WA 98104.

Abbreviations: CN, calcineurin; NMDA, N-methyl-D-aspartate; P, preexposed; NP, non-preexposed.

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