Research ArticlesAutism

Increased Gene Dosage of Ube3a Results in Autism Traits and Decreased Glutamate Synaptic Transmission in Mice

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Science Translational Medicine  05 Oct 2011:
Vol. 3, Issue 103, pp. 103ra97
DOI: 10.1126/scitranslmed.3002627

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Linking a Ligase to Autism

Autism spectrum disorder is highly heritable, but the genetic contribution is complex and heterogeneous. One chromosomal region, 15q11-13, when duplicated or tripled, often causes autism, accounting for up to 3% of autism risk. But we still cannot explain how even this relatively powerful autism predictor leads to the behavioral changes seen in the disease.

To begin to understand these gene-to-behavior links, the authors created mice that carry, like the 15q11-13 autistic patients, double and triple doses of an E3 ubiquitin protein ligase called Ube3a. This gene is not the only one in this region but it is of particular interest because it is expressed solely from the maternal allele in neurons and is deficient in Angelman syndrome. Mice carrying a triple dose of Ube3a showed abnormalities in behavior that are the mouse equivalent of the three cardinal features of autism: Like patients, the mice preferred less social interaction with their peers than controls. They also communicated with others infrequently, which in mice takes the form of fewer vocalizations upon encountering a new mouse of the same sex. And the stereotyped, repetitive behaviors of autism spectrum disorder were mimicked in the mice by increased self-grooming. The authors also showed that synaptic transmission in the brain cortex was abnormal, a clue as to how a ubiquitin ligase might alter behaviors, although we will certainly need to know which proteins are serviced by Ube3a to begin to trace the pathway from gene to behavior.

There are scores of identified and yet-to-be identified autism-associated genetic variations that individually or together may result in the behavioral and physical symptoms that make up autism spectrum disorder. Re-creation of some of these symptoms in mice by tripling the gene dosage of Ube3a reveals a key piece of the puzzle, but there are many yet to find and fit together.