Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism

Autism is a complex psychiatric illness that has received considerable attention as a developmental brain disorder. 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 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 autistic behavioral features such as 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 the neurons in mice with a paternal duplication. This first chromosome-engineered mouse model for autism replicates 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