Actin scaffolds as organizers of presynaptic function, assembly and plasticity across species

Abstract The presynapse is a highly specialized neuronal compartment whose organizational core, the active zone, coordinates the precisely regulated neurotransmitter release. The function, assembly, maturation and remodeling of presynapses are fundamental to brain function, underlying circuit development, synaptic plasticity and memory formation. Central to these processes is a dynamic actin cytoskeletal scaffold that integrates structural organization with synaptic vesicle exo- and endocytosis, thereby coupling molecular architecture to synaptic release. We summarize decades of work across vertebrate and invertebrate model systems to delineate how local, activity-dependent reorganization of the actin cytoskeletal modulates presynaptic function, assembly, and plasticity. We depict the molecular mechanism by which actin networks coordinate, in a developmental stage-dependent manner, nearly every part of the synaptic vesicle cycle and include a focus on myosin family proteins, as actin-based motor protein. Furthermore, we review the bidirectional interplay between presynaptic active zone proteins and the local presynaptic actin network. Finally, we focus on the role of actin scaffolds in synaptogenesis and how local actin regulation is coupled to nanoscale active zone organization and large-scale presynaptic terminal structure at the uniquely accessible and mechanistically informative Drosophila neuromuscular junction.