Identifying genetic risk for autism spectrum disorder (ASD) using organoids

The risk for autism spectrum disorder has been associated with hundreds of genes. However, the extent of changes in the human brain as a result of mutations in these genes and the contribution of specific genes remains unclear. Additionally, the manifestation of these changes varies across individuals. The symptoms of autism usually appear during the first two years of life, which is why it is described as a developmental disorder. 

Researchers from Harvard and MIT developed cortical brain organoid models using different human induced pluripotent stem cell lines. These organoids were profiled from one month to six months to document and show the presence of neurogenesis and the presence of different cell types, including neurons, astroglia, and interneurons. They proceeded to use these organoids to understand the effect of specifically three genes that have repeatedly emerged in the studies to find risk factors for ASD.  All three genes have been associated with neurodevelopmental disorders, including macrocephaly (larger head circumference). When the researchers studied the effect of mutations in these genes in the organoids, they found that all three mutations led to premature generation of neurons that produced gamma-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system (CNS). In addition, the neuronal activity, visualized by imaging Calcium signaling in the organoids, also showed a reduction. Then the researchers sought to investigate if these changes in the development of neuronal lineages occurred due to similar downstream molecular pathways. To understand this, they performed RNA-sequencing and proteome analysis. Interestingly, they found little overlap in the affected proteins in the three mutations. 

Thus, they found that while the three ASD-risk genes led to similar effects in terms of asynchronous or premature development of specific classes of neurons (GABAergic neurons) and reduced circuit activity; there was a divergence in terms of downstream molecular targets.  These findings can help scientists understand autism spectrum disorder more clearly, and could possibly help provide insights on how different genes contribute to the pathology of ASD.