Dscam1 Controls Presynaptic Terminal Size to Regulate Synaptic Structure and Function in a Central Motor Circuit

The Drosophila giant fiber system is a well-characterized escape circuit that enables precise investigation of synaptic development and function. Here, we examined the role of the cell adhesion molecule Dscam1 in shaping presynaptic architecture and supporting circuit performance. Using RNAi-mediated knockdown of Dscam1 in giant fiber interneurons, we observed reduced presynaptic terminal volume, smaller synapse interfaces, and reduced levels of electrical (Shak-B) and chemical (Bruchpilot) synaptic proteins. Despite this reduction in overall abundance, protein localization and density remained unchanged. Functionally, Dscam1 knockdown impaired circuit performance, both increasing latency and reducing success at high frequency demand. Correlation and principal component analysis of our data set show that anatomical variables, particularly presynaptic terminal size, best predicted circuit output. These findings identify Dscam1 as a key developmental regulator of presynaptic terminal size, linking early axon terminal elaboration to adult synaptic function in a central motor circuit. More broadly, our results exemplify a volumetric scaling model where available presynaptic area constrains the distribution of synaptic proteins, both electrical and chemical. Significance StatementProper circuit function requires not only the presence of synaptic proteins but also sufficient synaptic space to accommodate them. This study shows that Dscam1 is necessary for normal presynaptic terminal size in a central motor circuit, and when knocked down, constrains synapse size, functional protein content, and subsequently synapse function. These findings highlight a structural mechanism by which developmental regulators can set the capacity for mature synaptic transmission. More generally, our results provide a framework for investigating whether mammalian DSCAM plays a similar role in defining presynaptic capacity and ensuring robust circuit function.