New Screening Tech Used to Gain Insights into ASD-Associated Risk Genes

USC scientists used RosetteArray technology, a screening tool developed at the University of Wisconsin Madison that uses stem cells to generate embryonic forebrain or spinal cord tissue structures called neural rosettes, to delve into the complexities of the growing human brain. The tool offers an invaluable window into early human central nervous system development as well as insights into how genetic mutations linked to autism affect early stages of human brain development.

In the study published in Nature Neuroscience, researchers used RosetteArray technology to explore mutations in the SYNGAP1 gene associated with autism spectrum disorder.

SYNGAP1 mutations have long been associated with risk factors for autism spectrum disorder, epilepsy, neurodevelopmental disability and more, but until now the gene has mainly been studied in animal models and the studies focused on the impact of SYNGAP1 on synapses.

In their new SYNGAP1 autism study, senior author Giorgia Quadrato and her lab used RosetteArray technology to grow neural rosettes from healthy human cells as well as from the cells of a patient with a disease-causing variant in SYNGAP1. By analyzing these young, developing neural organoids, the team determined that human radial glia cells can express SYNGAP1. When SYNGAP1 is mutated, it leads to disrupted organization of the cortical plate, an early brain structure that gives rise to the cerebral cortex. This shows that SYNGAP1-related brain disorders can arise through non-synaptic mechanisms.

“Simply being able to model early human development, in this case brain and spinal cord formation, gives you a very powerful platform to try to improve human health,” explained Randolph Ashton, co-developer of RosetteArray. “We’ve been surprised to see the effects of neurological disease-causing mutations in the earliest stages of these tissues’ formation. RosetteArray models approximately four to six weeks post conception, and we’re learning that you can start to see markers for autism then, which is a disease that people typically aren’t diagnosed with until post two years of age. So, the fact that we can see this very early in our model of human development is amazing.”