Causally linking UBE3A misexpression to altered circuit dynamics controlling skilled movements

PROJECT SUMMARY Misregulation of the 15q11-q13 chromosomal region is particularly consequential for neurodevelopment. Maternal copy number increases in 15q11-q13 cause duplication 15q (Dup15q) syndrome, a major subtype of autism spectrum disorder, while maternal (but not paternal) 15q11-q13 deletions cause the neurodevelopmental disorder Angelman syndrome (AS). There are ~20 genes in the 15q11-q13 region, but only UBE3A is expressed exclusively from the maternal allele in mature neurons, hence it is thought to be the main genetic driver for AS and Dup15q syndrome. Motor deficits are among the earliest and most impactful clinical phenotypes in AS and Dup15q syndrome, although the precise manifestation differs by disorder. We currently lack an understanding of how UBE3A misexpression alters neural circuit dynamics to impair movement control. Here we will test the central hypothesis that the motor phenotypes resulting from UBE3A misexpression are caused by altered dynamics in specific neural circuits. We will use mouse models to identify the impact of varying Ube3a copy number on motor brain networks during the acquisition and production of a skilled reach-to-grasp movement that requires planning, action sequencing, sensory-guided corrections, and adaptation. Accordingly, this project will identify rules that govern the complex relationship between Ube3a gene dosage, motor deficits, and distributed brain network formation and function. Finally, we will test a translationally relevant gene therapy to normalize UBE3A expression in relevant motor circuits and restore typical motor function. Towards these goals, we will complete three aims: (1) establish the impact of Ube3a copy number on skilled movements, (2) establish the impact of Ube3a copy number on distributed neuronal dynamics, and (3) causally link circuit-specific normalization of UBE3A expression to neural dynamics and skilled movements. The successful completion of these aims is expected to guide the development of safe and efficacious therapeutic approaches for ameliorating motor deficits in Angelman and Dup15q syndromes.