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

Tripling the dosage of an autism- and Angelman syndrome–related gene in mice results in reduced glutamatergic synaptic transmission and autism behavioral traits. 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. People with autism spectrum disorder are characterized by impaired social interaction, reduced communication, and increased repetitive behaviors. The disorder has a substantial genetic component, and recent studies have revealed frequent genome copy number variations (CNVs) in some individuals. A common CNV that occurs in 1 to 3% of those with autism—maternal 15q11-13 duplication (dup15) and triplication (isodicentric extranumerary chromosome, idic15)—affects several genes that have been suggested to underlie autism behavioral traits. To test this, we tripled the dosage of one of these genes, the ubiquitin protein ligase Ube3a, which is expressed solely from the maternal allele in mature neurons, and reconstituted the three core autism traits in mice: defective social interaction, impaired communication, and increased repetitive stereotypic behavior. The penetrance of these autism traits depended on Ube3a gene copy number. In animals with increased Ube3a gene dosage, glutamatergic, but not GABAergic, synaptic transmission was suppressed as a result of reduced presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling. These results suggest that Ube3a gene dosage may contribute to the autism traits of individuals with maternal 15q11-13 duplication and support the idea that increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission.