Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

Abstract

A strong candidate gene for schizophrenia and major mental disorders, disrupted-inschizophrenia 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.

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

“…It may be necessary to explore the utility of temporal or spatial genetic knockdowns to gain information about the importance of a number of genes in schizophrenia. Recent work with DISC1 confirms the value of this approach (Hikida et al, 2007;Pletnikov et al, 2007).…”

The DISC locus in psychiatric illness

“…Although both groups identified increased lateral ventricle size in the absence of any change in total brain volume, Hikida et al 52 detected this abnormality only at 6 weeks of age and demonstrated, rather surprisingly, that by 3 months (when the transgene is no longer expressed) there is no detectable difference in lateral ventricle size between wildtype and transgenic animals. Pletnikov et al, 53 however, detected the increased lateral ventricle size in adult mice. Hikida et al 52 also found evidence for loss or reversal of normal brain asymmetry in animals expressing the transgene.…”

“…Within this developmental window, transgene expression is similar to that of endogenous Disc1 in the forebrain, although endogenous Disc1 is also present at other locations throughout the brain and throughout development into adulthood (see subsequent sections). Ross and co-workers (Pletnikov et al 53 ) used essentially the same approach, but with an inducible expression system directed by the CaMKII promoter, and were able to detect expression from as early as embryonic day 15, suggesting that the CaMKII promoter may not be faithfully regulated.…”

“…Hikida et al 52 also found evidence for loss or reversal of normal brain asymmetry in animals expressing the transgene. Pletnikov et al 53 performed a detailed histological examination and detected no abnormalities of morphology, layering or cytoarchitecture within the hippocampus and cortex. The fact that there were significant differences between these superficially similar transgenic models begs a number of questions about the mechanism that only further analysis and direct comparison will resolve.…”

Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity

“…The Disc1/Ndel1 interaction also competitively inhibits Ndel1 oligopeptidase activity (Hayashi et al, 2010). Finally, the balanced translocation disrupting the DISC1 gene described by Millar et al (2000) generates a truncated form of Disc1 protein reported to be unable to bind to Ndel1 Kamiya et al, 2005;Pletnikov et al, 2008).…”