Myosin 15 participates in assembly and remodeling of the presynapse.

The assembly and remodeling of presynaptic specializations are of crucial importance for circuit development and adaptive behaviors. However, the mechanisms by which presynaptic material is locally distributed within synaptic terminals and across consuming active zones remain poorly understood. In this study, we identify the conserved unconventional class XV myosin, Myo15, an actin motor, as a novel regulator of presynaptic assembly and remodeling in Drosophila. Myo15 localizes to the local actin and microtubule network at synaptic terminals. Depletion of Myo15 resulted in smaller individual active zones, increased active zone density, and irregular terminal morphology, while its overexpression enlarged individual active zones and promoted synaptic terminal growth. Myo15 was found to modulate the actin meshwork, and deletion of its microtubule-binding MyTH4 domain rendered the protein nonfunctional. Furthermore, Myo15 was essential for presynaptic functional homeostatic plasticity and memory consolidation. These findings suggest that Myo15 plays a critical role in the assembly and remodeling of presynaptic active zones.