The fusion of neurotransmitter-filled vesicles during synaptic transmission is balanced by endocytotic membrane retrieval. Despite extensive research, the speed and mechanisms of synaptic vesicle endocytosis have remained controversial. Here, we establish low-noise time-resolved membrane capacitance measurements that allow monitoring changes in surface membrane area elicited by single action potentials and stronger stimuli with high-temporal resolution at physiological temperature in individual bona-fide mature central synapses. We show that single action potentials trigger very rapid endocytosis, retrieving presynaptic membrane with a time constant of 470 ms. This fast endocytosis is independent of clathrin but mediated by dynamin and actin. In contrast, stronger stimuli evoke a slower mode of endocytosis that is clathrin, dynamin, and actin dependent. Furthermore, the speed of endocytosis is highly temperature dependent with a Q10 of ~3.5. These results demonstrate that distinct molecular modes of endocytosis with markedly different kinetics operate at central synapses. Membrane retrieval of fused synaptic vesicles by endocytosis is essential for synaptic function. Using time-resolved presynaptic membrane capacitance measurements at physiological temperature, Delvendahl et al. show that single action potentials trigger fast and clathrin-independent endocytosis at mature central synapses.
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