High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways
Hellen Weinschutz Mendes, Uma Neelakantan, Yunqing Liu, Sarah E. Fitzpatrick, Tianying Chen, Weimiao Wu, April Pruitt, David Jin, Priyanka Jamadagni, Marina Carlson, Cheryl Lacadie, Kristen Enriquez, Ningshan Li, Dejian Zhao, Sundas Ijaz, Catalina Sakai, Christina Szi, Brendan Rooney, Marcus Ghosh, Ijeoma Nwabudike, Andrea Gorodezky, Sumedha Chowdhury, Meeraal Zaheer, Sarah McLaughlin, Joseph M. Fernandez, Jia Qian Wu, Jeffrey Eilbott, Brent Vander Wyk, Jason Rihel, Xenophon Papademetris, Zuoheng Wang, Ellen J. Hoffman
Abstract
Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.