Operant behavior is reliably impaired in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive impairment, absent speech, seizures, motor and sleep impairments, and caused by loss of function of the maternal copy of the UBE3A gene. Modeling the AS phenotype in preclinical models across behavioral domains is critical for testing of new therapeutics. Our previous work reported behavioral phenotypes in male Ube3a m-/p+ (AS model) mice on a cognitive-like operant extinction task. Here, we evaluated operant task performance in male and female Ube3a m-/p+ mice across two cohorts, and correlated operant performance with performance on a battery of other widely used behavioral tests for Ube3a mutants. Ube3a m-/p+ mice showed impairments in both the acquisition and extinction phases of operant testing that were not sex-specific. Inclusion of operant testing in the existing Ube3a m-/p+ behavioral battery was feasible and improved clustering of genotypes in principal component space. Overall, operant acquisition and extinction testing is a reliable approach to quantify cognitive-like learning impairments in Ube3a m-/p+ mice. Operant testing should be considered as part of a broad toolbox for evaluating the effectiveness of AS treatments preclinically.