Evidence for a primary endocytic vesicle involved in synaptic vesicle biogenesis

The regulated release of neurotransmitters at synapses is mediated by the f usion of neurotransmitter-filled synaptic vesicles with the plasma membrane . Continuous synaptic activity relies on the constant recycling of synaptic vesicle proteins into newly formed synaptic vesicles. At least two differe nt mechanisms are presumed to mediate synaptic Vesicle biogenesis at the sy napse as follows: direct retrieval of synaptic vesicle proteins and lipids from the plasma membrane, and indirect passage of synaptic vesicle proteins through an endosomal intermediate. We have identified a vesicle population with the characteristics of a primary endocytic vesicle responsible for th e recycling of synaptic vesicle proteins through the indirect pathway. We f ind that synaptic vesicle proteins colocalize in this vesicle with a variet y of proteins known to recycle from the plasma membrane through the endocyt ic pathway, in eluding three different glucose transporters, GLUT1, GLUT3, and GLUT4, and the transferrin receptor. These vesicles differ from "classi cal" synaptic vesicles in their size and their generic protein content, ind icating that they do not discriminate between synaptic vesicle-specific pro teins and other recycling proteins. We propose that these vesicles deliver synaptic vesicle proteins that have escaped internalization by the direct p athway to endosomes, where they are sorted from other recycling proteins an d packaged into synaptic vesicles.