Cell Type-Specific Contributions of UBE3A to Angelman Syndrome Behavioral Phenotypes

Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of expression of the maternal <i>UBE3A</i> allele and is characterized by a constellation of impactful neurologic symptoms. While previous work has uncovered outsized contributions of GABAergic neuron-selective <i>Ube3a</i> deletion to seizure susceptibility and electroencephalography (EEG) phenotypes in a mouse model of AS, the neuronal populations governing a broader range of behaviors have not been studied. Here, we used male and female mice to test the consequences of <i>Ube3a</i> deletion from GABAergic or glutamatergic neurons across a well-characterized battery of AS-relevant behaviors. Surprisingly, we observed deficits in numerous motor and innate behaviors in mice with glutamatergic <i>Ube3a</i> deletion and relatively few consequences of GABAergic <i>Ube3a</i> deletion. Furthermore, genetic <i>Ube3a</i> reinstatement in glutamatergic neurons rescued multiple motor and innate behaviors. When tested for sleep-wake behaviors, the selective loss of <i>Ube3a</i> from glutamatergic neurons disrupted sleep similarly to that of AS model mice (<i>Ube3a^m-/p+</i> ), and glutamatergic <i>Ube3a</i> reinstatement overcame the lack of active cycle "siesta" and decreased REM phenotypes observed in AS model mice. Altogether, this work demonstrates a major role of glutamatergic neuron UBE3A loss in mediating multiple AS behavioral features, suggesting a divergence from the circuitry underlying enhanced seizure susceptibility. Our findings imply that neuronal cell type-agnostic UBE3A reinstatement is likely required for successful AS genetic therapies-with reinstatement of UBE3A in GABAergic neurons necessary for overcoming epileptic and EEG phenotypes, and reinstatement in glutamatergic neurons necessary for overcoming most other behavioral phenotypes.