Abstract
A strong candidate gene for schizophrenia and major mental disorders, disrupted-in-schizophrenia 1 (DISC1) was first described in a large Scottish family in which a balanced chromosomal translocation segregates with schizophrenia and other psychiatric illnesses. The translocation mutation may result in loss of DISC1 function via haploinsufficiency or dominant-negative effects of a predicted mutant DISC1 truncated protein product. DISC1 has been implicated in neurodevelopment, including maturation of the cerebral cortex. To evaluate the neuronal and behavioral effects of mutant DISC1, the Tet-off system under the regulation of the CAMKII promoter was used to generate transgenic mice with inducible expression of mutant human DISC1 (hDISC1) limited to forebrain regions, including cerebral cortex, hippocampus and striatum. Expression of mutant hDISC1 was not associated with gross neurodevelopmental abnormalities, but led to a mild enlargement of the lateral ventricles and attenuation of neurite outgrowth in primary cortical neurons. These morphological changes were associated with decreased protein levels of endogenous mouse DISC1, LIS1 and SNAP-25. Compared to their sex-matched littermate controls, mutant hDISC1 transgenic male mice exhibited spontaneous hyperactivity in the open field and alterations in social interaction, and transgenic female mice showed deficient spatial memory. The results show that the neuronal and behavioral effects of mutant hDISC1 are consistent with a dominant-negative mechanism, and are similar to some features of schizophrenia. The present mouse model may facilitate the study of aspects of the pathogenesis of schizophrenia.
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Acknowledgements
We thank Dr Akira Sawa (Department of Psychiatry and Behavioral Sciences, Program in Molecular Psychiatry, Johns Hopkins University School of Medicine) and the members of his laboratory, Drs Atsushi Kamiya, Koko Ishizuka and Takatoshi Hikida, for their generous gift of the plasmids and helpful discussions of the initial cloning and immunoprecipitation experiments. We appreciate the support of Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine. This work was supported by the grants from the Stanley Medical Research Institute (MVP), National Alliance for Research on Schizophrenia and Depression (NARSAD, Distinguished Investigator Award) (CAR), RO1EB003543 (SM) and MH077792-01A1 (MVP).
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Pletnikov, M., Ayhan, Y., Nikolskaia, O. et al. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry 13, 173–186 (2008). https://doi.org/10.1038/sj.mp.4002079
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DOI: https://doi.org/10.1038/sj.mp.4002079
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