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      Calcium/synaptotagmin-evoked compound fusion increases quantal size and synaptic strength

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          Abstract

          Exocytosis at synapses generally refers to fusion between vesicles and the plasma membrane 1. Although compound fusion between vesicles 2, 3 was proposed at ribbon-type synapses 4, 5, whether it exists, how it is mediated, and what role it plays at conventional synapses remain unclear. Here we addressed this issue at a nerve terminal containing conventional active zones. High potassium application and high frequency firing induced giant capacitance up-steps reflecting exocytosis of vesicles larger than regular ones, followed by giant down-steps reflecting bulk endocytosis. They also induced giant vesicle-like structures, as observed with electron microscopy, and giant miniature EPSCs (mEPSCs) reflecting more transmitter release. Calcium and its sensor for vesicle fusion, synaptotagmin, were required for these giant events. After high frequency firing, calcium/synaptotagmin-dependent mEPSC size increase was paralleled by calcium/synaptotagmin-dependent post-tetanic potentiation (PTP). These results suggest that calcium/synaptotagmin mediates compound fusion between vesicles, that exocytosis of compound vesicles increases quantal size which enhances synaptic strength and thus contributes to the generation of PTP, and that exocytosed compound vesicles may be retrieved via bulk endocytosis. We suggest to include a new vesicle cycling route, compound exocytosis followed by bulk endocytosis, into models of synapses, where currently only vesicle fusion with the plasma membrane is considered ( Fig. S1) 1.

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          Most cited references30

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          Short-term synaptic plasticity.

          Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca(2+)]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases of synaptic enhancement, as well as the interpretation of statistical changes in transmitter release and roles played by other factors such as alterations in presynaptic Ca(2+) influx or postsynaptic levels of [Ca(2+)]i. Synaptic depression dominates enhancement at many synapses. Depression is usually attributed to depletion of some pool of readily releasable vesicles, and various forms of the depletion model are discussed. Depression can also arise from feedback activation of presynaptic receptors and from postsynaptic processes such as receptor desensitization. In addition, glial-neuronal interactions can contribute to short-term synaptic plasticity. Finally, we summarize the recent literature on putative molecular players in synaptic plasticity and the effects of genetic manipulations and other modulatory influences.
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            EVIDENCE FOR RECYCLING OF SYNAPTIC VESICLE MEMBRANE DURING TRANSMITTER RELEASE AT THE FROG NEUROMUSCULAR JUNCTION

            When the nerves of isolated frog sartorius muscles were stimulated at 10 Hz, synaptic vesicles in the motor nerve terminals became transiently depleted. This depletion apparently resulted from a redistribution rather than disappearance of synaptic vesicle membrane, since the total amount of membrane comprising these nerve terminals remained constant during stimulation. At 1 min of stimulation, the 30% depletion in synaptic vesicle membrane was nearly balanced by an increase in plasma membrane, suggesting that vesicle membrane rapidly moved to the surface as it might if vesicles released their content of transmitter by exocytosis. After 15 min of stimulation, the 60% depletion of synaptic vesicle membrane was largely balanced by the appearance of numerous irregular membrane-walled cisternae inside the terminals, suggesting that vesicle membrane was retrieved from the surface as cisternae. When muscles were rested after 15 min of stimulation, cisternae disappeared and synaptic vesicles reappeared, suggesting that cisternae divided to form new synaptic vesicles so that the original vesicle membrane was now recycled into new synaptic vesicles. When muscles were soaked in horseradish peroxidase (HRP), this tracerfirst entered the cisternae which formed during stimulation and then entered a large proportion of the synaptic vesicles which reappeared during rest, strengthening the idea that synaptic vesicle membrane added to the surface was retrieved as cisternae which subsequently divided to form new vesicles. When muscles containing HRP in synaptic vesicles were washed to remove extracellular HRP and restimulated, HRP disappeared from vesicles without appearing in the new cisternae formed during the second stimulation, confirming that a one-way recycling of synaptic membrane, from the surface through cisternae to new vesicles, was occurring. Coated vesicles apparently represented the actual mechanism for retrieval of synaptic vesicle membrane from the plasma membrane, because during nerve stimulation they proliferated at regions of the nerve terminals covered by Schwann processes, took up peroxidase, and appeared in various stages of coalescence with cisternae. In contrast, synaptic vesicles did not appear to return directly from the surface to form cisternae, and cisternae themselves never appeared directly connected to the surface. Thus, during stimulation the intracellular compartments of this synapse change shape and take up extracellular protein in a manner which indicates that synaptic vesicle membrane added to the surface during exocytosis is retrieved by coated vesicles and recycled into new synaptic vesicles by way of intermediate cisternae.
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              Direct measurement of specific membrane capacitance in neurons.

              The specific membrane capacitance (C(m)) of a neuron influences synaptic efficacy and determines the speed with which electrical signals propagate along dendrites and unmyelinated axons. The value of this important parameter remains controversial. In this study, C(m) was estimated for the somatic membrane of cortical pyramidal neurons, spinal cord neurons, and hippocampal neurons. A nucleated patch was pulled and a voltage-clamp step was applied. The exponential decay of the capacitative charging current was analyzed to give the total membrane capacitance, which was then divided by the observed surface area of the patch. C(m) was 0.9 microF/cm(2) for each class of neuron. To test the possibility that membrane proteins may alter C(m), embryonic kidney cells (HEK-293) were studied before and after transfection with a plasmid coding for glycine receptor/channels. The value of C(m) was indistinguishable in untransfected cells and in transfected cells expressing a high level of glycine channels, indicating that differences in transmembrane protein content do not significantly affect C(m). Thus, to a first approximation, C(m) may be treated as a "biological constant" across many classes of neuron.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                1 April 2009
                7 May 2009
                7 November 2009
                : 459
                : 7243
                : 93-97
                Affiliations
                [1 ]National Institute of Neurological Disorders and Stroke, 35 Convent Dr., Bldg 35, Rm. 2B-1012, Bethesda, Maryland 20892
                [2 ]Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, 2121 W. Holcombe Blvd., Box 1100, Houston, Texas 77030
                Author notes
                [*]

                equal contribution

                Article
                nihpa102684
                10.1038/nature07860
                2768540
                19279571
                b7182355-3e18-40b5-9d97-a50fda69e173
                History
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: Z99 NS999999 ||NS
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