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• W2023290266 abstract "During prolonged stimulation, fusion of thousands of synaptic vesicles poses a challenge for the temporal and spatial coordination of exocytosis and endocytosis. In this issue of Neuron, Hosoi and colleagues reveal that [Ca2+]i-microdomains trigger compensatory endocytosis. Block of endocytosis enhances short-term depression by delaying vesicle recruitment to docking sites on active zones. During prolonged stimulation, fusion of thousands of synaptic vesicles poses a challenge for the temporal and spatial coordination of exocytosis and endocytosis. In this issue of Neuron, Hosoi and colleagues reveal that [Ca2+]i-microdomains trigger compensatory endocytosis. Block of endocytosis enhances short-term depression by delaying vesicle recruitment to docking sites on active zones. The relinquishment of neurotransmitters from nerve terminals requires some prior assembly. First, synaptic vesicles, laden with transmitter, need to translocate from a cytoplasmic reservoir to specific contact sites on the plasma membrane. A complex meshwork of actin filaments, tethers, and scaffolding proteins mediates vesicle recruitment to a small area called the active zone (Gundelfinger et al., 2003Gundelfinger E.D. Kessels M.M. Qualmann B. Nat. Rev. Mol. Cell Biol. 2003; 4: 127-139Crossref PubMed Scopus (192) Google Scholar). Here, vesicles are captured and tethered to presynaptic dense projections, and some are placed in close proximity to Ca2+ channels. Through a series of poorly understood priming reactions, a subset of docked vesicles becomes fully competent for exocytosis. These primed vesicles constitute a readily releasable pool, poised for fast exocytosis and awaiting only one final signal: the opening of nearby Ca2+ channels. A large macromolecular complex is thus required for the fast and focal exocytosis of synaptic vesicles (Verhage and Sørensen, 2008Verhage M. Sørensen J.B. Traffic. 2008; 9: 1414-1424Crossref PubMed Scopus (146) Google Scholar). Vesicular membrane is then retrieved via an elaborate endocytosis machinery that needs to be quickly assembled and disassembled as vesicles cycle from the plasma membrane to the cytoplasm and then back to empty docking sites on the active zone. What are the mechanisms that regulate the coupling between exocytosis and endocytosis? In this issue of Neuron, Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar address this question by measuring membrane capacitance changes at the calyx of Held nerve terminal. Capacitance changes are proportional to net changes in cell surface area and thus constitute a measure of synaptic exo- and endocytosis. The authors show that a series of depolarizing steps evokes a capacitance jump (exocytosis) followed by a decay of capacitance back to baseline that is blocked by compounds that interfere with clathrin-mediated endocytosis. This compensatory decay of capacitance thus constitutes a bona fide measure of the rate of synaptic endocytosis. Furthermore, the rate of capacitance decay varies with the amount of evoked exocytosis. Short depolarizing pulses that produce a small capacitance jump are followed by relatively fast endocytosis (τ ≤ 10 s), suggesting that abundant endocytic “resources” are available under these conditions. Physiologically, this may occur during low-frequency action potential firing when a single vesicle may fuse at a given active zone (Figure 1A), resulting in minimal disruption of the active zone machinery. Accordingly, rates of endocytosis have been found to be fast after short depolarizations at several different nerve terminals (Heidelberger et al., 2002Heidelberger R. Zhou Z.-Y. Matthews G. J. Neurophysiol. 2002; 88: 2509-2517Crossref PubMed Scopus (45) Google Scholar). However, the rate of endocytosis becomes progressively slower after larger bouts of exocytosis, perhaps because the internal reservoir of endocytic proteins becomes more and more depleted (Figure 1B; Balaji et al., 2008Balaji J. Armbruster M. Ryan T.A. J. Neurosci. 2008; 28: 6742-6749Crossref PubMed Scopus (68) Google Scholar). To study further the coupling between exocytosis and slow endocytosis, Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar reasoned that microdomain-[Ca2+]i rises, which are known to trigger exocytosis, may also influence compensatory endocytosis at active zones. They tested this hypothesis with three straightforward sets of experiments. They found that lowering the external Ca2+ concentration slowed the rate of endocytosis. Additionally, dialysis of the fast Ca2+ buffer BAPTA into the calyx terminal blocked slow endocytosis, while elevation of free intracellular calcium concentrations to 20 μM via flash photolysis of caged Ca2+ promoted endocytosis at a rate comparable to that observed after a train of depolarizing pulses. Together, these results compellingly demonstrate that local [Ca2+]i close to that of Ca2+ channel clusters triggers slow, clathrin-mediated endocytosis at the calyx of Held. This result is surprising in light of previous data suggesting that elevated Ca2+ levels only promote a fast component of endocytosis that follows after large amounts of cumulative exocytosis (Wu et al., 2005Wu W. Xu J. Wu X.-S. Wu L.-G. J. Neurosci. 2005; 25: 11676-11683Crossref PubMed Scopus (98) Google Scholar). However, the flash photolysis experiments reported here do find that higher elevations of Ca2+ lead to faster rates of endocytosis (Wu et al., 2005Wu W. Xu J. Wu X.-S. Wu L.-G. J. Neurosci. 2005; 25: 11676-11683Crossref PubMed Scopus (98) Google Scholar). Whether several forms of endocytosis regulated by different Ca levels exist at the calyx terminal under diverse physiological stimulation protocols remains an open question and further work will be needed to clarify this issue. Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar then examine the molecular machinery responsible for compensatory endocytosis and present evidence that synaptobrevin/VAMP, a key v-SNARE-type protein for exocytosis, is also involved in regulating slow endocytosis. Interestingly, previous studies proposed that synaptobrevin/VAMP is involved in fast endocytosis (Deak et al., 2004Deak F. Schoch S. Liu X. Südhof T.C. Kavalali E.T. Nat. Cell Biol. 2004; 6: 1102-1108Crossref PubMed Scopus (178) Google Scholar), whereas synaptotagmin, the Ca2+-sensor for exocytosis, mediates slow endocytosis (Poskanzer et al., 2003Poskanzer K.E. Marek K.W. Sweeney S.T. Davis G.W. Nature. 2003; 426: 559-563Crossref PubMed Scopus (213) Google Scholar). Given the multistep task at hand, the high degree of accuracy required, and the speed of recycling, it is perhaps not surprising that some proteins may play a dual role in both the exocytic and the endocytic limbs of the vesicle cycle. Thus, some proteins involved in exocytosis may have specific epitopes for the binding of endocytic adaptor proteins. They may thereby seed the process of membrane retrieval, helping endocytic proteins distinguish between fused vesicular membrane destined for reinternalization and nerve terminal membrane proteins and lipids that should remain on the presynaptic plasma membrane. Finally, Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar suggest that slow endocytosis regulates short-term plasticity. The in vivo calyx of Held is a nerve terminal that can fire spontaneously at very high rates. During high-frequency stimulation, the probability of multivesicular release rises, and at some small bouton-type nerve terminals containing a single active zone, up to five vesicles may fuse with the plasma membrane (Oertner et al., 2002Oertner T.G. Sabatini B.L. Nimchinsky E.A. Svoboda K. Nat. Neurosci. 2002; 5: 657-664PubMed Google Scholar). Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar now show that a short 100 Hz tetanus of action-potential-like depolarizations increases membrane capacitance by about 200 fF (or 20 μm2), corresponding to the fusion of about 2500 synaptic vesicles. These data suggest that, on average, five synaptic vesicles fuse at the 500 active zones of the calyx of Held (Sätzler et al., 2002Sätzler K. Söhl L.F. Bollmann J.H. Borst J.G. Frotscher M. Sakmann B. Lübke J.H. J. Neurosci. 2002; 22: 10567-10579PubMed Google Scholar), during short tetanic stimulation. If these vesicles collapse completely, the area of a single active zone will increase by almost 50%. With even stronger stimulation, the entire readily releasable pool can fuse, almost doubling the size of the active zone. This may transiently disrupt the normal modus operandi of active zones. For example, the number of local endocytic molecules may not be sufficient to support fast endocytosis, ATP stores may become depleted as Na+ and Ca2+ ions are pumped out of the terminal, key proteins needed for vesicle tethering/docking may be pushed away from docking sites, and the average distance between any remaining docked vesicles to Ca2+ channels may be significantly increased (Figure 1B). Conventional active zones may thus have a limited capacity to cope with large amounts of release. Indeed, even at ribbon-type synapses, which are thought to have par excellence a large capacity for continuous exocytosis, there is evidence that active zones may become disorganized and depleted of synaptic vesicles after continuous stimulation (Hull et al., 2006Hull C. Studholme K. Yazulla S. von Gersdorff H. J. Neurophysiol. 2006; 96: 2025-2033Crossref PubMed Scopus (62) Google Scholar, Jackman et al., 2009Jackman S.L. Choi S.Y. Thoreson W.B. Rabl K. Bartoletti T.M. Kramer R.H. Nat. Neurosci. 2009; 12: 303-310Crossref PubMed Scopus (115) Google Scholar). Multivesicular release may thus resemble more a tsumani than a gentle rippling over the plasma membrane. How do nerve terminals cope with this sudden stress to their release machinery, and can it contribute to short-term depression? Through a series of elegant paired-recording experiments, Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar demonstrate that blocking slow endocytosis significantly slows the rate of recovery from short-term depression and reduces the amplitude of steady-state EPSCs during a tetanic stimulation train. These results thus establish a direct link between exocytosis and endocytosis. Previously, such a link had been elusive (but see Lou et al., 2008Lou X. Paradise S. Ferguson S.M. De Camilli P. Proc. Natl. Acad. Sci. USA. 2008; 105: 17555-17560Crossref PubMed Scopus (47) Google Scholar), and studies at ribbon-type synapses had even indicated that block of slow endocytosis does not lead necessarily to a loss in the capacity for repeated bouts of exocytosis (Heidelberger et al., 2002Heidelberger R. Zhou Z.-Y. Matthews G. J. Neurophysiol. 2002; 88: 2509-2517Crossref PubMed Scopus (45) Google Scholar). Perhaps ribbon-type active zones are specialized to avoid traffic jams in continuous vesicle cycling and may have mechanisms that promote a rapid spatial and temporal uncoupling of exocytosis to endocytosis. Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar propose that the enhanced short-term depression resulting from block of endocytosis is due to delayed recruitment of release-ready vesicles, perhaps because active zones become disrupted during copious exocytosis and cannot be cleared fast enough to maintain continuously high rates of release (Figure 1B). The replenishment rate of the readily releasable pool of vesicles is not involved. So the rate-limiting step in release appears to be the fresh recruitment of vesicles to docking sites and their priming for exocytosis. This is a surprising and provocative postulate since vesicle pool depletion, and the replenishment rates of depleted pools have dominated much of our thinking about the mechanisms of short-term depression. Like most major advances, the paper of Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar raises more questions than it can answer. What is the identity of the Ca2+ sensor that triggers slow clathrin-dependent endocytosis? Could it be that an isoform of a Janus-faced synaptogamin promotes both exocytosis and endocytosis? Are there multiple Ca2+ sensors for different forms of endocytosis at other synapses? Can fast, clathrin-independent endocytosis occur after low-frequency stimulation protocols, and does bulk endocytosis predominate after very prolonged stimulation (de Lange et al., 2003de Lange R.P.J. de Roos A.D.G. Borst J.G.G. J. Neurosci. 2003; 23: 10164-10173Crossref PubMed Google Scholar)? Clearly, more work remains to be done. However, the study by Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar adds a wealth of new data and ideas on the mechanisms of endocytosis and short-term plasticity. Together with the concepts of “positional priming” and “molecular priming” for exocytosis (Neher and Sakaba, 2008Neher E. Sakaba T. Neuron. 2008; 59: 861-872Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar), and of the clearance rates of disrupted active zones, the findings of Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63 (this issue): 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar may force us to abandon some long-standing assumptions about how endocytosis is regulated, how it is coupled to exocytosis, and how synapses function when heavy demands are placed on them for continuous exocytosis. Calcium Dependence of Exo- and Endocytotic Coupling at a Glutamatergic SynapseHosoi et al.NeuronJuly 30, 2009In BriefThe mechanism coupling exocytosis and endocytosis remains to be elucidated at central synapses. Here, we show that the mechanism linking these two processes is dependent on microdomain-[Ca2+]i similar to that which triggers exocytosis, as well as the exocytotic protein synaptobrevin/VAMP. Furthermore, block of endocytosis has a limited, retrograde action on exocytosis, delaying recruitment of release-ready vesicles and enhancing short-term depression. This effect sets in so rapidly that it cannot be explained by the nonavailability of recycled vesicles. 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• W2023290266 title "Traffic Jams during Vesicle Cycling Lead to Synaptic Depression" @default.
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