Chromosomal Engineering of a 15q11-13 Duplication Mouse Model of Autism

Background:   Autism is a complex psychiatric illness which has received considerable attention as a developmental brain disorder. Substantial evidence suggests that chromosomal abnormalities contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism.

Objectives: To create a chromosome-engineered mouse model analogous to human 15q11-13 duplication.

Methods: 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.

Results: Mice with a paternal duplication display autistic behavioral features such as poor social interaction and stereotypical behavior, and exhibit abnormal ultrasonic vocalizations. The analysis on a MBII52 snoRNA within these duplicated region reveals that the editing ratio of serotonin 2c receptor (5-HT2cR) pre-mRNA and intracellular Ca²⁺ responses by a 5-HT2cR agonist are altered in the paternally duplicated neurons.

Conclusions: 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 be a founder mouse for forward genetics of autistic disease and an invaluable tool for its therapeutic development.