Empty clathrin cages in neurons

Clathrin has established roles in endocytosis and short-range vesicle trafficking, where clathrin cages envelop membrane-pits on the plasma membrane or vesicles exchanging between Golgi/endosomes, and this canonical role of clathrin is thought to be conserved in all cell types including neurons. However, the polarized architecture of neurons creates unique demands on clathrin recruitment and function, requiring clathrin to operate in presynapses that are far from sites of protein synthesis in the soma and act within the limited membrane area of periactive-zones in a nonconstitutive manner-responding to cues such as neuronal activity. Recent studies have revealed unusual long-lasting clathrin assemblies that are transported along axons and captured at synapses, congregating around synaptic vesicle clusters. Unexpectedly, cryo-electron tomography shows empty cages of clathrin at synapses that do not enclose any membrane. This short review discusses recent findings related to the structure and dynamics of neuronal clathrin and frames some new questions that have emerged.