Pilot Study to Understand Skilled Motor Impairments in Angelman Syndrome
Motor deficits are common and debilitating, but not well-understood, symptoms of Angelman syndrome. AS results from the loss of the UBE3A gene. The development and study of animal models of AS that lack the same gene has advanced our understanding of brain abnormalities associated with AS and has led to exciting progress in genetic therapies. However, relating motor deficits to specific brain abnormalities has remained a challenge. Understanding the specific brain mechanisms that lead to motor deficits is likely to provide insight into related symptoms, such as speech impairments or learning disability.
Motivated by recent advances in the ability to precisely track the movements of animals while measuring neural activity across multiple brain areas, this project is aimed at developing a detailed understanding of how motor deficits are related to brain function in AS. By studying animal models of AS that lack the UBE3A gene, we will, first, associate motor impairments with brain abnormalities and then, second, reintroduce the UBE3A gene into the brain at different developmental timepoints to establish the ability to recover motor deficits and related brain mechanisms.
This project aims to discover the neural mechanisms underlying motor deficits in AS, which has the potential to generalize and shed light on cognitive and speech symptoms. This understanding will inform ongoing therapy approaches and may motivate new approaches for individuals with AS.
Why This Study is Important
It is important to understand which brain regions cause the different challenges individuals with AS face. Different therapeutics are better at reaching certain brain regions, and so this understanding may help us think about why a therapeutic works or doesn’t work to relieve certain problems. Dr. Hantman’s study focuses on fine motor skills. These are important for self care (i.e. feeding, etc..), reaching for and moving objects, and may even impact language development.
This project utilized a genetic mouse line in which Ube3a was removed from the brain. The mice are trained to perform reaching actions in which they reach and grab for food rewards and – as they perform these tasks – their movements and brain activity are precisely measured. It was determined that the mice lacking UBE3A perform reaching movements much slower than typical mice.
The study team looked at brain activity across many different regions to try and identify specific patterns of brain activity that are unique to mice lacking UBE3A that may explain this unique slow reaching strategy. Preliminary findings are that the cerebellum, a brain region critical for processing sensory information during movement, has distinct dynamics during reaching movements in mice lacking UBE3A mice. To determine if these distinct dynamics are responsible for the differences in reaching movements in mice lacking UBE3A mice, researchers then restore expression of UBE3A only in the cerebellum and observe whether reaching movements are performed faster, more similar to control mice. The researchers hope is that by identifying the neural correlate of this specific reaching phenotype in mice lacking UBE3A, they can shed light on a brain region in individuals with Angelman syndrome that may be producing distinct dynamics compared to neurotypical individuals.