Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in the Ube3a Deletion Rat Model of Angelman Syndrome

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and a happy, excitable demeanor with frequent laughter. We sought to elucidate a preclinical outcome measure in male and female rats that addressed communication abnormalities of AS and other neurodevelopmental disorders in which communication is atypical and/or lack of speech is a core feature. We discovered, and herein report for the first time, excessive laughter-like 50 kHz ultrasonic emissions in the Ube3a(m)(at/pat+ )rat model of AS, which suggests an excitable, playful demeanor and elevated positive affect, similar to the demeanor of individuals with AS. Also in line with the AS phenotype, Ube3a(m)(at/pat+) rats demonstrated aberrant social interactions with a novel partner, distinctive gait abnormalities, impaired cognition, an underlying LTP deficit, and profound reductions in brain volume. These unique, robust phenotypes provide advantages compared with currently available mouse models and will be highly valuable as outcome measures in the evaluation of therapies for AS.

Automated summary

Angelman syndrome is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor deficits, impaired communication, and happy demeanor; researchers discovered excessive laughter-like ultrasonic emissions in a rat model of AS, suggesting an excitable, playful personality similar to individuals with AS. The unique phenotypes of this rat model, including aberrant social interactions and cognitive impairments, provide advantages for evaluating therapies for AS compared to available mouse models.