Journal
CELL
Volume 137, Issue 7, Pages 1235-1246Publisher
CELL PRESS
DOI: 10.1016/j.cell.2009.04.024
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Funding
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology
- Neuroinformatics Japan Center
- Institute for Bioinformatics Research and Development
- Core Research for Evolutional Science and Technology
- Mitsubishi Foundation
- Mother and Child Health Foundation
- Mitsubishi Pharma Research Foundation
- Takeda Science Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Sony Corporation
- Nippon Boehringer Ingelheim Co., Ltd
- Wellcome Trust
- Grants-in-Aid for Scientific Research [21300121] Funding Source: KAKEN
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Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca2+ responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.
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