Several key barriers exist to unraveling the mechanistic etiologies of autism spectrum disorder (ASD). There is increasing appreciation that ASD pathology, while genetically heterogeneous, may result from disruptions to common multicellular interactions that impact cortical circuitry and alter excitatory/inhibitory (E/I) balance. Duplication or triplication of maternally inherited 15q11-13, the chromosomal location where UBE3A resides, is one of the most common genetic variants linked to ASD. UBE3A is an E6 ubiquitin ligase that controls the levels of key synaptic proteins, and UBE3A activity has been shown to control E/I balance in the cerebral cortex of mice,.
To date, almost all of our understanding of the roles of UBE3A in the brain comes from studies in mouse models and human cell cultures. While crucial insights have been gained from this work, the human brain is a highly complex organ, and these model systems do not fully recapitulate human brain development and physiology. To address these concerns, Albert Keung and others have generated cerebral organoids that model many features of human cortical brain development and exhibit polarized cortical tissue among other anatomical structures found in the human brain.
Keung proposes to introduce modern genetic tools and sensors into this cerebral organoid culture system to create multicellular models of human neurodevelopment and disease. Keung and colleagues will track the spatiotemporal expression of UBE3A and its effects on neural activity in diverse cell types within developing wild-type cerebral organoids to identify key developmental periods and cell types in which UBE3A might be most important. While the team plans to initially focus on studies of UBE3A, the tools that are developed will be broadly useful for studying ASD and other neurodevelopmental disorders.
