Abstract：

Autism spectrum disorder (ASD) is a complex psychiatric illness that has received considerable attention as a developmental brain disorder. Substantial evidence suggests that chromosomal abnormalities including copy number variations (CNV) contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in ASD. We 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 (patDp/+) display autistic-like behavioral features such as poor social interaction and behavioral inflexibility, and exhibit abnormal ultrasonic vocalizations. This chromosome-engineered mouse model for ASD (15q dup mouse) seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human CNV. This 15q dup mouse is the first CNV model of ASD and a founder mouse for forward genetics of a developmental brain disorder. Our multi-dimensional approach reveals that 15q dup mice show impaired spine phenotypes, abnormality in serotonin, and excitatory/inhibitory imbalance. The rescue experiment during the developmental stage suggests the significance of serotonin on neural and behavioral development. I’ll talk about our recent analyses mainly on the 15 dup mice and hopefully add our new direction towards understanding the pathophysiology of ASD and development of its therapeutic intervention. Multi-dimensional analyses including cutting-edge technologies will provide new pathophysiological bases for ASD.

References:

Takumi T and Tamada K: CNV biology in neurodevelopmental disorders. Curr Opin Neurobiol. 48: 183-192, 2018.

Nakai N et al.: Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-12 CNV mice. Science Adv. 3: e1603001, 2017.

Nakatani J et al.: Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 137: 1235-1246, 2009.