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Biology Articles » Neurobiology » Neurobiology of Diseases & Aging » Gene malfunctions cause schizophrenia, depression symptoms in mice
Researchers have demonstrated for the first time that malfunction of a gene that had been associated with schizophrenia and depression does indeed cause symptoms of those disorders. They said their findings in mice offer a possible animal model for developing treatments for schizophrenia and depression. Also, they said their findings support the theory that the two disorders share common genetic mechanisms.
Steven Clapcote, David Porteous, John Roder, and colleagues reported their findings in the May 3, 2007 issue of the journal Neuron, published by Cell Press.
In their experiments, the researchers sought to explore the consequences of mutating a gene called "Disrupted in schizophrenia 1" (DISC1), which had been found in one family to be associated with schizophrenia, bipolar disorder, and major depression.
The researchers' theory was that different mutant variations of DISC1 might have different pathological effects. To test this theory, the researchers screened a large population of mouse mutants to isolate two with different mutations in DISC1.
They found that, indeed, one of the mutant mouse strains exhibited behavioral abnormalities and memory deficiencies resembling the symptoms of schizophrenia in humans. Additionally, these symptoms could be alleviated in the mice by antipsychotic drugs.
Similarly, the other mutant mouse strain showed behaviors that reflected depressive symptoms. These symptoms could be alleviated by an antidepressant, found the researchers.
Both types of DISC1 mutant mice exhibited the same kind of reduced brain volume seen in people with schizophrenia and depression, the researchers found. Also, both types showed biochemical abnormalities in the function of the protein produced by the DISC1 gene.
The researchers concluded that the different effects of antipsychotic and antidepressant drugs on the two mutant strains "might provide clues to effective medications for these patient groups. Indeed, these mice could represent a model system to explore novel treatment and preventative strategies for certain symptoms of major mental illness," they wrote.
"We have shown that two independent missense mutations in mouse Disc1 elicit distinct physiological, pharmacological, neuroanatomical, and behavioral phenotypes, which when taken together are strikingly consistent with the emerging picture from clinical and basic studies of DISC1 as a common genetic and biologically plausible risk factor for major mental illness," concluded Clapcote and colleagues. They wrote that "our findings lend further credence to the growing recognition that schizophrenia and bipolar disorder share, at least in part, common genetic etiologies and thus underlying molecular mechanisms."
The researchers include Steven J. Clapcote and Tatiana V. Lipina of Mount Sinai Hospital in Toronto, Canada; J. Kirsty Millar, Shaun Mackie, Sheila Christie, Fumiaki Ogawa, and David J. Porteous of University of Edinburgh Centre for Molecular Medicine in Edinburgh, UK; Jason P. Lerch and Keith Trimble of Hospital for Sick Children in Toronto, Canada; Masashi Uchiyama, Yoshiyuki Sakuraba, Hideki Kaneda, Toshihiko Shiroishi, and Yoichi Gondo of RIKEN Genomic Sciences Center in Yokohama, Japan; Miles D. Houslay of University of Glasgow of Glasgow, UK; R. Mark Henkelman and John G. Sled of Hospital for Sick Children and University of Toronto in Toronto, Canada; John C. Roder of Mount Sinai Hospital and University of Toronto in Toronto, Canada.
This study was supported by grants-in-aid to J.C.R. from the Canadian Institutes of Health Research (CIHR; GMH-79044) and the National Alliance for Research on Schizophrenia and Depression, to Y.G. from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and to D.J.P., J.K.M., and M.D.H. from the Medical Research Council (UK). J.C.R. holds a Canada Research Chair.
Clapcote et al.: "Behavioral Phenotypes of Disc1 Missense Mutations in Mice." Publishing in Neuron 54, 387–402, May 3, 2007. DOI 10.1016/j.neuron.2007.04.015. www.neuron.org.
Cell Press. May 2007.
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