Curbside recycling at the synapse

hen John Heuser finished medical school at the height of the Vietnam War he was immediately eligible for the draft. Luckily for him, and for cell biology, he fulfilled his military service at the National Institutes of Health (NIH) in the United States Public Health Service. It was there that he brought the concept of " membrane recycling " to light. He brought to Thomas Reese's lab at the NIH a postdoctoral project he had started with Sir Bernard Katz at University College, London—an attempt to capture a picture of neurotransmitter " quanta " being released as Katz had proposed. The only approach available to him at the time, Heuser recalls, " was to stimulate the nerve like hell and throw it into fixative. " But he W soon realized, " the chances were still almost zero of catching it. " The method, however, gave him images of nerve terminals at the frog neuro-muscular junction that had " weird vesicles and mem-branous cisternae " inside. Heuser, now at Washington University (St. Louis, Missouri), recalls that other scientists who saw the images said the overstimulated nerves were " disgusting, " " just destroyed, " and " not relevant to anything. " Heuser had a hunch, however, that the internal structures were not just signs of degradation, but instead were products of endocytosis. Together with Tom Reese, he decided to investigate his idea using horseradish peroxidase (HRP), the endo-cytic tracer that was just coming into its own as a powerful marker in electron microscopy. They stimulated frog nerve terminals while bathing them in extracellular HRP and found that HRP first appeared in clathrin-coated vesicles that formed from the nerve terminal plasma membrane. These vesicles then coalesced, and the HRP showed up in the internal cisternae (now known to be endosomes). Finally, the HRP ended up in a new population of synaptic vesicles as they reformed (Heuser and Reese, 1973). This evidence, along with the pair's meticulous accounting of membrane fluxes between synaptic vesicles, plasma membrane, and cisternae, argued strongly for a rapid recycling of synaptic vesicle membrane via endocytosis. The model figure at the end of the paper headed straight into textbooks and the paper received more than 1,300 citations. Heuser says he chose the term " recycling " deliberately, both because of the new environmental movement and because it made a critical distinction: " The synaptic vesicle is not like a …