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.