Ca2+ Dependence of Synaptic Vesicle Endocytosis

Ca2+-dependent synaptic vesicle recycling is essential for structural homeostasis of synapses and maintenance of neurotransmission. Although, the executive role of intrasynaptic Ca2+ transients in synaptic vesicle exocytosis is well established, identifying the exact role of Ca2+ in endocytosis has been difficult. In some studies, Ca2+ has been suggested as an essential trigger required to initiate synaptic vesicle retrieval, whereas others manipulating synaptic Ca2+ concentrations reported a modulatory role for Ca2+ leading to inhibition or acceleration of endocytosis. Molecular studies of synaptic vesicle endocytosis, on the other hand, have consistently focused on the roles of Ca2+-calmodulin dependent phosphatase calcineurin and synaptic vesicle protein synaptotagmin as potential Ca2+ sensors for endocytosis. Most studies probing the role of Ca2+ in endocytosis have relied on measurements of synaptic vesicle retrieval after strong stimulation. Strong stimulation paradigms elicit fusion and retrieval of multiple synaptic vesicles and therefore can be affected by several factors besides the kinetics and duration of Ca2+ signals that include the number of exocytosed vesicles and accumulation of released neurotransmitters thus altering fusion and retrieval processes indirectly via retrograde signaling. Studies monitoring single synaptic vesicle endocytosis may help resolve this conundrum as in these settings the impact of Ca2+ on synaptic fusion probability can be uncoupled from its putative role on synaptic vesicle retrieval. Future experiments using these single vesicle approaches will help dissect the specific role(s) of Ca2+ and its sensors in synaptic vesicle endocytosis.