By Charlene N. Rivera-Bonet, Waisman Science Writer
Four Waisman Center investigators will dig deeper into the function of genes implicated in autism and brain development with support from the prestigious Simons Foundation 2022 Pilot Award. Xinyu Zhao, PhD, professor of neuroscience and Jenni & Kyle Professor of Novel Neurodevelopmental Diseases, Qiang Chang, PhD, professor of medical genetics and neurology and director of the Waisman Center, Daifeng Wang, PhD, assistant professor of biostatistics and medical informatics and computer sciences, and André Sousa, PhD, assistant professor of neuroscience, will each contribute their broad range of expertise in this comprehensive approach to study autism and brain development.
The Simons Foundation Autism Research Initiative (SFARI) looks to improve the understanding, diagnosis and treatment of autism spectrum disorder (ASD) through the funding of innovative research. Their pilot grant is designed to support new exploratory ideas that are considered high risk but have good potential for impactful results.
With the support of this two-year grant, the Waisman quartet will investigate autism using marmosets, a non-human primate model that closely resembles the human brain. In particular, they will focus on how autism risk genes affect the brain’s prefrontal cortex during early development. This region is known for its role in working memory, planning, decision-making, language, and creative intelligence, which are highly derived in primates. Some of these functions are significantly impaired in autism.
The results of this study may reveal how deficiencies in these autism risk genes alter the development and function of the fetal primate brain.
Their approach involves genetically manipulating three ASD genes in marmoset brain slices. They will then apply a cutting-edge technology called Patch-Seq, which measures the electrical activity and gene expression profile of neurons to identify the functions of these autism genes in driving neuronal development. They will also perform gene expression and chromatin accessibility analyses of single cells in the prefrontal cortex after knocking down each autism gene. By performing an integrative analysis of these multimodal data, they will predict how genes work together to influence neuronal electrical activity in development and test the hypothesis that ASD genes are critical for functional maturation of the prefrontal cortex.
Jon Levine, PhD, professor of neuroscience, will join the team on these efforts. “Our complementary expertise and unique resources at UW allow us to take a bold step towards addressing fundamental challenges in neuroscience and establish tools for investigating gene functions in human brain diseases. This collaborative environment is really incredible,” Zhao says.
This is one of a very few SFARI grants issued to UW-Madison. “We’re really excited about this Simons Foundation pilot project,” Zhao says. “This is a prestigious and highly competitive award, which further highlights the strength of our university.” Recent technological advances have identified many genes implicated in brain disorders, however how these genes affect brain development and functions, especially in primates remain unknown. The innovative work funded by this Simons grant will establish methods that can be broadly applicable to many neurological diseases.
By becoming part of this distinguished foundation that includes autism researchers from all over the world, the Waisman scientists hope to expand their network of researchers, as well as find more opportunities for additional and expanded funding from the foundation. “This grant really opens the door to future possibilities,” Zhao says.
The research team contributing to this collaborative project include scientists Yu Gao, PhD, Qiping Dong, PhD, and Shuang Liu, PhD, as well as the following trainees: postdoctoral fellow Kalpana Arachchilage, PhD, graduate student Jie Sheng, and research interns Danielle Schmidt and Moosa Syed.
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