Pathogenic mutations in clathrin heavy chain disrupt synapse architecture and learning in Drosophila

Clathrin-mediated endocytosis is essential for neural development and function. Recent studies have linked de novo mutations in the clathrin heavy-chain gene to a range of neurodevelopmental disorders. In this study, we have modeled two pathogenic mutations, L1047P and W1108R, in Drosophila melanogaster and examined their effects on vesicle dynamics, ligand uptake, neuronal development, and memory formation. Our data show that expression of these mutant forms of clathrin heavy chain results in reduced survival and defective learning when expressed ubiquitously or exclusively in neurons. These mutations also disrupted vesicle dynamics and reduced ligand uptake under conditions of heat stress. While no obvious defects in neuronal morphology and function were observed at the larval neuromuscular junction, we noticed significant disruptions in the expression of markers associated with synapse maturation. Overall, our study establishes a model that can provide insights into the cellular basis of clathrin heavy-chain-related neurodevelopmental disorders.