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  • Review Article
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The sequence of events that underlie quantal transmission at central glutamatergic synapses

Nature Reviews Neuroscience volume 8, pages 597–609 (2007)Cite this article

Key Points

  • There has been remarkable recent progress in our understanding of the sequence of steps that mediate chemical transmission at mammalian central glutamatergic synapses. This work provides insight into how neurotransmitter is released and how the quantal response is generated.

  • Work on large central synapses has made it possible to voltage-clamp the presynaptic terminal, to control the Ca2+ concentration and to monitor release. This work confirms earlier studies in the squid giant axon showing that the current through voltage-dependent Ca2+ channels that triggers release occurs on the falling phase of the action potential.

  • The Ca2+ that triggers release occurs in a microdomain near the Ca2+ channels. This Ca2+ elevation is sensed by the molecule synaptotagmin 1. It appears that the synaptic vesicle membrane is already partially fused with the plasma membrane and awaits the activation of synaptotagmin. When this occurs, a fusion pore opens. Whether this pore is like a protein channel or is lipid-lined remains to be resolved.

  • The size of the fusion pore can vary and this determines the rate at which the neurotransmitter diffuses into the synaptic cleft. Modulation of fusion pore size is likely to be important for regulation.

  • The resulting activation of AMPA channels in the postsynaptic membrane depends on the channel's properties and much has been learnt about this through structural, molecular and electrophysiological experiments. Glutamate can cause either activation or inactivation of AMPA channels. To be effectively activated, the glutamate concentration in the synaptic cleft must be high, a condition that only holds near the site of vesicle release.

  • Each vesicle that is released generates a quantal response in the postsynaptic cell. Many of the factors that shape the quantal response and make it reproducible are now understood. At some synapses multiple vesicles are released, allowing fluctuations in transmission efficacy.

Abstract

The properties of synaptic transmission were first elucidated at the neuromuscular junction. More recent work has examined transmission at synapses within the brain. Here we review the remarkable progress in understanding the biophysical and molecular basis of the sequential steps in this process. These steps include the elevation of Ca2+ in microdomains of the presynaptic terminal, the diffusion of transmitter through the fusion pore into the synaptic cleft and the activation of postsynaptic receptors. The results give insight into the factors that control the precision of quantal transmission and provide a framework for understanding synaptic plasticity.

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Figure 1: Steps in the process of chemical synaptic transmission
Figure 2: Timing of steps in transmission
Figure 3: Synapse structure and the localization of activated AMPA channels.
Figure 4: Vesicle fusion and fusion pores.
Figure 5: Determinants of quantal transmission

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References

  1. Katz, B. Neural transmitter release: from quantal secretion to exocytosis and beyond. The Fenn Lecture. J. Neurocytol. 25, 677–686 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Heuser, J. E. et al. Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. J. Cell Biol. 81, 275–300 (1979).

    Article  CAS  PubMed  Google Scholar 

  3. Heuser, J. E. & Reese, T. S. Structural changes after transmitter release at the frog neuromuscular junction. J. Cell Biol. 88, 564–580 (1981).

    Article  CAS  PubMed  Google Scholar 

  4. Stiles, J. R., Van Helden, D., Bartol, T. M. Jr, Salpeter, E. E. & Salpeter, M. M. Miniature endplate current rise times less than 100 microseconds from improved dual recordings can be modeled with passive acetylcholine diffusion from a synaptic vesicle. Proc. Natl Acad. Sci. USA 93, 5747–5752 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Borst, J. G., Helmchen, F. & Sakmann, B. Pre- and postsynaptic whole-cell recordings in the medial nucleus of the trapezoid body of the rat. J. Physiol. 489, 825–840 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Geiger, J. R. & Jonas, P. Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons. Neuron 28, 927–939 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Llinas, R., Steinberg, I. Z. & Walton, K. Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse. Biophys. J. 33, 323–351 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Augustine, G. J., Charlton, M. P. & Smith, S. J. Calcium entry and transmitter release at voltage-clamped nerve terminals of squid. J. Physiol. 367, 163–181 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu, L. G., Westenbroek, R. E., Borst, J. G., Catterall, W. A. & Sakmann, B. Calcium channel types with distinct presynaptic localization couple differentially to transmitter release in single calyx-type synapses. J. Neurosci. 19, 726–736 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Iwasaki, S., Momiyama, A., Uchitel, O. D. & Takahashi, T. Developmental changes in calcium channel types mediating central synaptic transmission. J. Neurosci. 20, 59–65 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Reid, C. A., Bekkers, J. M. & Clements, J. D. Presynaptic Ca2+ channels: a functional patchwork. Trends Neurosci. 26, 683–687 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Momiyama, A. & Takahashi, T. Development of inhibitory synaptic currents in rat spinal neurons. Ann. NY Acad. Sci. 707, 447–448 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Mintz, I. M., Sabatini, B. L. & Regehr, W. G. Calcium control of transmitter release at a cerebellar synapse. Neuron 15, 675–688 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Sabatini, B. L. & Regehr, W. G. Timing of neurotransmission at fast synapses in the mammalian brain. Nature 384, 170–172 (1996). A study that provides a different view of the timing of steps leading to vesicle release. This study suggests that release can occur before the falling phase of the action potenital, making a much shorter synaptic delay possible.

    Article  CAS  PubMed  Google Scholar 

  15. Sabatini, B. L. & Regehr, W. G. Timing of synaptic transmission. Annu. Rev. Physiol. 61, 521–542 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. McDonough, S. I., Mintz, I. M. & Bean, B. P. Alteration of P-type calcium channel gating by the spider toxin ω-Aga-IVA. Biophys. J. 72, 2117–2128 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Llinas, R., Sugimori, M. & Silver, R. B. Microdomains of high calcium concentration in a presynaptic terminal. Science 256, 677–679 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Serulle, Y., Sugimori, M. & Llinas, R. R. Imaging synaptosomal calcium concentration microdomains and vesicle fusion by using total internal reflection fluorescent microscopy. Proc. Natl Acad. Sci. USA 104, 1697–1702 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stanley, E. F. The calcium channel and the organization of the presynaptic transmitter release face. Trends Neurosci. 20, 404–409 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Harlow, M. L., Ress, D., Stoschek, A., Marshall, R. M. & McMahan, U. J. The architecture of active zone material at the frog's neuromuscular junction. Nature 409, 479–484 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Pumplin, D. W., Reese, T. S. & Llinás, R. Are the presynaptic membrane particles the calcium channels? Proc. Natl Acad. Sci. USA 78, 7210–7213 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shahrezaei, V., Cao, A. & Delaney, K. R. Ca2+ from one or two channels controls fusion of a single vesicle at the frog neuromuscular junction. J. Neurosci. 26, 13240–13249 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ohana, O. & Sakmann, B. Transmitter release modulation in nerve terminals of rat neocortical pyramidal cells by intracellular calcium buffers. J. Physiol. 513, 135–148 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Burnashev, N. & Rozov, A. Presynaptic Ca2+ dynamics, Ca2+ buffers and synaptic efficacy. Cell Calcium 37, 489–495 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Schneggenburger, R. & Neher, E. Intracellular calcium dependence of transmitter release rates at a fast central synapse. Nature 406, 889–893 (2000). An elegant study that measured the release attributable to defined Ca2+ changes in the presynaptic terminal.

    Article  CAS  PubMed  Google Scholar 

  26. Bollmann, J. H., Sakmann, B. & Borst, J. G. Calcium sensitivity of glutamate release in a calyx-type terminal. Science 289, 953–957 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Bollmann, J. H. & Sakmann, B. Control of synaptic strength and timing by the release-site Ca2+ signal. Nature Neurosci. 8, 426–434 (2005). A clever strategy was used to mimic the brief Ca2+ elevation produced by an action potential and to study the resulting transmitter release.

    Article  CAS  PubMed  Google Scholar 

  28. Bennett, M. K., Calakos, N. & Scheller, R. H. Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257, 255–259 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Sheng, Z. H., Rettig, J., Cook, T. & Catterall, W. A. Calcium-dependent interaction of N-type calcium channels with the synaptic core complex. Nature 379, 451–454 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Jarvis, S. E. & Zamponi, G. W. Masters or slaves? Vesicle release machinery and the regulation of presynaptic calcium channels. Cell Calcium 37, 483–488 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Meinrenken, C. J., Borst, J. G. & Sakmann, B. Local routes revisited: the space and time dependence of the Ca2+ signal for phasic transmitter release at the rat calyx of Held. J. Physiol. 547, 665–689 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Meinrenken, C. J., Borst, J. G. & Sakmann, B. Calcium secretion coupling at calyx of held governed by nonuniform channel-vesicle topography. J. Neurosci. 22, 1648–1667 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wadel, K., Neher, E. & Sakaba, T. The coupling between synaptic vesicles and Ca2+ channels determines fast neurotransmitter release. Neuron 53, 563–575 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Fedchyshyn, M. J. & Wang, L. Y. Developmental transformation of the release modality at the calyx of Held synapse. J. Neurosci. 25, 4131–4140 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhai, R. G. & Bellen, H. J. The architecture of the active zone in the presynaptic nerve terminal. Physiology (Bethesda) 19, 262–270 (2004).

    Google Scholar 

  36. Zampighi, G. A. et al. Conical electron tomography of a chemical synapse: vesicles docked to the active zone are hemi-fused. Biophys. J. 91, 2910–2918 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Phillips, G. R. et al. The presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution. Neuron 32, 63–77 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Felmy, F., Neher, E. & Schneggenburger, R. The timing of phasic transmitter release is Ca2+-dependent and lacks a direct influence of presynaptic membrane potential. Proc. Natl Acad. Sci. USA 100, 15200–15205 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dodge, F. A. Jr & Rahamimoff, R. Co-operative action of calcium ions in transmitter release at the neuromuscular junction. J. Physiol. 193, 419–432 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wolfel, M. & Schneggenburger, R. Presynaptic capacitance measurements and Ca2+ uncaging reveal submillisecond exocytosis kinetics and characterize the Ca2+ sensitivity of vesicle pool depletion at a fast CNS synapse. J. Neurosci. 23, 7059–7068 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zucker, R. S. & Regehr, W. G. Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Bischofberger, J., Engel, D., Frotscher, M. & Jonas, P. Timing and efficacy of transmitter release at mossy fiber synapses in the hippocampal network. Pflugers Arch. 453, 361–372 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Korogod, N., Lou, X. & Schneggenburger, R. Presynaptic Ca2+ requirements and developmental regulation of posttetanic potentiation at the calyx of Held. J. Neurosci. 25, 5127–5137 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Isaacson, J. S. & Walmsley, B. Counting quanta: direct measurements of transmitter release at a central synapse. Neuron 15, 875–884 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Diamond, J. S. & Jahr, C. E. Asynchronous release of synaptic vesicles determines the time course of the AMPA receptor-mediated EPSC. Neuron 15, 1097–1107 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Millet, O., Bernado, P., Garcia, J., Rizo, J. & Pons, M. NMR measurement of the off rate from the first calcium-binding site of the synaptotagmin I C2A domain. FEBS Lett. 516, 93–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Collin, T. et al. Developmental changes in parvalbumin regulate presynaptic Ca2+ signaling. J. Neurosci. 25, 96–107 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sudhof, T. C. The synaptic vesicle cycle. Annu. Rev. Neurosci. 27, 509–547 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Geppert, M. et al. Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse. Cell 79, 717–727 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Nishiki, T. & Augustine, G. J. Dual roles of the C2B domain of synaptotagmin I in synchronizing Ca2+-dependent neurotransmitter release. J. Neurosci. 24, 8542–8550 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nishiki, T. & Augustine, G. J. Synaptotagmin I synchronizes transmitter release in mouse hippocampal neurons. J. Neurosci. 24, 6127–6132 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Fernandez-Chacon, R. et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 410, 41–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Stewart, B. A., Mohtashami, M., Trimble, W. S. & Boulianne, G. L. SNARE proteins contribute to calcium cooperativity of synaptic transmission. Proc. Natl Acad. Sci. USA 97, 13955–13960 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hua, Y. & Scheller, R. H. Three SNARE complexes cooperate to mediate membrane fusion. Proc. Natl Acad. Sci. USA 98, 8065–8070 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Montecucco, C., Schiavo, G. & Pantano, S. SNARE complexes and neuroexocytosis: how many, how close? Trends Biochem. Sci. 30, 367–372 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Xu, Y., Zhang, F., Su, Z., McNew, J. A. & Shin, Y. K. Hemifusion in SNARE-mediated membrane fusion. Nature Struct. Mol. Biol. 12, 417–422 (2005).

    Article  CAS  Google Scholar 

  58. Reese, C., Heise, F. & Mayer, A. Trans-SNARE pairing can precede a hemifusion intermediate in intracellular membrane fusion. Nature 436, 410–414 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Giraudo, C. G., Eng, W. S., Melia, T. J. & Rothman, J. E. A clamping mechanism involved in SNARE-dependent exocytosis. Science 313, 676–680 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Tang, J. et al. A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis. Cell 126, 1175–1187 (2006). This paper provides insights into the steps that make the vesicle primed for release.

    Article  CAS  PubMed  Google Scholar 

  61. Schaub, J. R., Lu, X., Doneske, B., Shin, Y. K. & McNew, J. A. Hemifusion arrest by complexin is relieved by Ca2+ –synaptotagmin I. Nature Struct. Mol. Biol. 13, 748–750 (2006). Direct measurements of membrane mixing provide unique insights into the fusion process.

    Article  CAS  Google Scholar 

  62. Zimmerberg, J., Akimov, S. A. & Frolov, V. Synaptotagmin: fusogenic role for calcium sensor? Nature Struct. Mol. Biol. 13, 301–303 (2006).

    Article  CAS  Google Scholar 

  63. Jackson, M. B. & Chapman, E. R. Fusion pores and fusion machines in Ca2+-triggered exocytosis. Annu. Rev. Biophys. Biomol. Struct. 35, 135–160 (2006). An excellent review of the issues regarding the mechanism by which the fusion pore is generated.

    Article  CAS  PubMed  Google Scholar 

  64. Han, X., Wang, C. T., Bai, J., Chapman, E. R. & Jackson, M. B. Transmembrane segments of syntaxin line the fusion pore of Ca2+-triggered exocytosis. Science 304, 289–292 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Han, X. & Jackson, M. B. Electrostatic interactions between the syntaxin membrane anchor and neurotransmitter passing through the fusion pore. Biophys. J. 88, L20–L22 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Almers, W. Exocytosis. Annu. Rev. Physiol. 52, 607–624 (1990).

    Article  CAS  PubMed  Google Scholar 

  67. He, L., Wu, X. S., Mohan, R. & Wu, L. G. Two modes of fusion pore opening revealed by cell-attached recordings at a synapse. Nature 444, 102–105 (2006). A technical breakthrough allows direct measurements of vesicle fusion and fusion pore formation at the secretory face of a central synapse.

    Article  CAS  PubMed  Google Scholar 

  68. Chen, X., Wang, L., Zhou, Y., Zheng, L. H. & Zhou, Z. 'Kiss-and-run' glutamate secretion in cultured and freshly isolated rat hippocampal astrocytes. J. Neurosci. 25, 9236–9243 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Klyachko, V. A. & Jackson, M. B. Capacitance steps and fusion pores of small and large-dense-core vesicles in nerve terminals. Nature 418, 89–92 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Harata, N. C., Aravanis, A. M. & Tsien, R. W. Kiss-and-run and full-collapse fusion as modes of exo-endocytosis in neurosecretion. J. Neurochem. 97, 1546–1570 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Harata, N. C., Choi, S., Pyle, J. L., Aravanis, A. M. & Tsien, R. W. Frequency-dependent kinetics and prevalence of kiss-and-run and reuse at hippocampal synapses studied with novel quenching methods. Neuron 49, 243–256 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Aravanis, A. M., Pyle, J. L. & Tsien, R. W. Single synaptic vesicles fusing transiently and successively without loss of identity. Nature 423, 643–647 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Ceccarelli, B., Hurlbut, W. P. & Mauro, A. Turnover of transmitter and synaptic vesicles at the frog neuromuscular junction. J. Cell Biol. 57, 499–524 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gandhi, S. P. & Stevens, C. F. Three modes of synaptic vesicular recycling revealed by single-vesicle imaging. Nature 423, 607–613 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Pawlu, C., DiAntonio, A. & Heckmann, M. Postfusional control of quantal current shape. Neuron 42, 607–618 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Burger, P. M. et al. Synaptic vesicles immunoisolated from rat cerebral cortex contain high levels of glutamate. Neuron 3, 715–720 (1989).

    Article  CAS  PubMed  Google Scholar 

  77. Raghavachari, S. & Lisman, J. E. Properties of quantal transmission at CA1 synapses. J. Neurophysiol. 92, 2456–2467 (2004). This paper used Monte-Carlo simulations to show how the glutamate released from a vesicle diffuses in the cleft and activates AMPA channels.

    Article  CAS  PubMed  Google Scholar 

  78. Tanaka, J. et al. Number and density of AMPA receptors in single synapses in immature cerebellum. J. Neurosci. 25, 799–807 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nielsen, T. A., DiGregorio, D. A. & Silver, R. A. Modulation of glutamate mobility reveals the mechanism underlying slow-rising AMPAR EPSCs and the diffusion coefficient in the synaptic cleft. Neuron 42, 757–771 (2004). This paper uses a clever combination of experimental manipulation and modelling to discern the diffusion coefficient of the neurotransmitter glutamate in the synpaptic cleft. This is an important parameter in determining the amplitude of synaptic responses.

    Article  CAS  PubMed  Google Scholar 

  80. Smith, M. A., Ellis-Davies, G. C. & Magee, J. C. Mechanism of the distance-dependent scaling of Schaffer collateral synapses in rat CA1 pyramidal neurons. J. Physiol. 548, 245–258 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Forti, L., Bossi, M., Bergamaschi, A., Villa, A. & Malgaroli, A. Loose-patch recordings of single quanta at individual hippocampal synapses. Nature 388, 874–878 (1997). A direct measurement of the quantal response at putatively single synapses showing that quantal responses have small variability.

    Article  CAS  PubMed  Google Scholar 

  82. Silver, R. A., Cull-Candy, S. G. & Takahashi, T. Non-NMDA glutamate receptor occupancy and open probability at a rat cerebellar synapse with single and multiple release sites. J. Physiol. 494, 231–250 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Liu, G., Choi, S. & Tsien, R. W. Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices. Neuron 22, 395–409 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. McAllister, A. K. & Stevens, C. F. Nonsaturation of AMPA and NMDA receptors at hippocampal synapses. Proc. Natl Acad. Sci. USA 97, 6173–6178 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Franks, K. M., Bartol, T. M. Jr. & Sejnowski, T. J. A Monte Carlo model reveals independent signaling at central glutamatergic synapses. Biophys. J. 83, 2333–2348 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Choi, S., Klingauf, J. & Tsien, R. W. Fusion pore modulation as a presynaptic mechanism contributing to expression of long-term potentiation. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 695–705 (2003). A review of experiments pointing to the importance of the mode of vesicle release in AMPA channel activation. Experiments suggesting a role for this process in synaptic plasticity are also reviewed.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Liao, D., Hessler, N. A. & Malinow, R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 (1995).

    Article  CAS  PubMed  Google Scholar 

  88. Bekkers, J. M., Richerson, G. B. & Stevens, C. F. Origin of variability in quantal size in cultured hippocampal neurons and hippocampal slices. Proc. Natl Acad. Sci. USA 87, 5359–5362 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hanse, E. & Gustafsson, B. Quantal variability at glutamatergic synapses in area CA1 of the rat neonatal hippocampus. J. Physiol. 531, 467–480 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sahara, Y. & Takahashi, T. Quantal components of the excitatory postsynaptic currents at a rat central auditory synapse. J. Physiol. 536, 189–197 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jonas, P., Major, G. & Sakmann, B. Quantal components of unitary EPSCs at the mossy fibre synapse on CA3 pyramidal cells of rat hippocampus. J. Physiol. 472, 615–663 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Franks, K. M., Stevens, C. F. & Sejnowski, T. J. Independent sources of quantal variability at single glutamatergic synapses. J. Neurosci. 23, 3186–3195 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Karunanithi, S., Marin, L., Wong, K. & Atwood, H. L. Quantal size and variation determined by vesicle size in normal and mutant Drosophila glutamatergic synapses. J. Neurosci. 22, 10267–10276 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Schikorski, T. & Stevens, C. F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J. Neurosci. 17, 5858–5867 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wall, M. J. & Usowicz, M. M. Development of the quantal properties of evoked and spontaneous synaptic currents at a brain synapse. Nature Neurosci. 1, 675–682 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Ulrich, D. & Luscher, H. R. Miniature excitatory synaptic currents corrected for dendritic cable properties reveal quantal size and variance. J. Neurophysiol. 69, 1769–1773 (1993).

    Article  CAS  PubMed  Google Scholar 

  97. Yamashita, T., Ishikawa, T. & Takahashi, T. Developmental increase in vesicular glutamate content does not cause saturation of AMPA receptors at the calyx of held synapse. J. Neurosci. 23, 3633–3638 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Magee, J. C. & Cook, E. P. Somatic EPSP amplitude is independent of synapse location in hippocampal pyramidal neurons. Nature Neurosci. 3, 895–903 (2000). This paper combines local dendritic recording and focal sucrose application to measure the mEPSC with minimal dendritic filtering. This provides the most constrained measurement of the time-course of the mEPSC.

    Article  CAS  PubMed  Google Scholar 

  99. Bornstein, J. C. Spontaneous multiquantal release at synapses in guinea-pig hypogastric ganglia: evidence that release can occur in bursts. J. Physiol. 282, 375–398 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Paulsen, O. & Heggelund, P. The quantal size at retinogeniculate synapses determined from spontaneous and evoked EPSCs in guinea-pig thalamic slices. J. Physiol. 480, 505–511 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Paulsen, O. & Heggelund, P. Quantal properties of spontaneous EPSCs in neurones of the guinea-pig dorsal lateral geniculate nucleus. J. Physiol. 496, 759–772 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Min, M. Y. & Appenteng, K. Multimodal distribution of amplitudes of miniature and spontaneous EPSPs recorded in rat trigeminal motoneurones. J. Physiol. 494, 171–182 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dennis, M. J., Harris, A. J. & Kuffler, S. W. Synaptic transmission and its duplication by focally applied acetylcholine in parasympathetic neurons in the heart of the frog. Proc. R. Soc. Lond. B Biol. Sci. 177, 509–539 (1971).

    Article  CAS  PubMed  Google Scholar 

  104. Liu, G. & Feldman, J. L. Quantal synaptic transmission in phrenic motor nucleus. J. Neurophysiol. 68, 1468–1471 (1992).

    Article  CAS  PubMed  Google Scholar 

  105. Edwards, F. A., Konnerth, A. & Sakmann, B. Quantal analysis of inhibitory synaptic transmission in the dentate gyrus of rat hippocampal slices: a patch-clamp study. J. Physiol. 430, 213–249 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Llano, I. et al. Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients. Nature Neurosci. 3, 1256–1265 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Melamed, N., Helm, P. J. & Rahamimoff, R. Confocal microscopy reveals coordinated calcium fluctuations and oscillations in synaptic boutons. J. Neurosci. 13, 632–649 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Emptage, N. J., Reid, C. A. & Fine, A. Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release. Neuron 29, 197–208 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Simkus, C. R. & Stricker, C. The contribution of intracellular calcium stores to mEPSCs recorded in layer II neurones of rat barrel cortex. J. Physiol. 545, 521–535 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Galante, M. & Marty, A. Presynaptic ryanodine-sensitive calcium stores contribute to evoked neurotransmitter release at the basket cell–Purkinje cell synapse. J. Neurosci. 23, 11229–11234 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sharma, G. & Vijayaraghavan, S. Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing. Neuron 38, 929–939 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Jack, J. J., Larkman, A. U., Major, G. & Stratford, K. J. Quantal analysis of the synaptic excitation of CA1 hippocampal pyramidal cells. Adv. Second Messenger Phosphoprotein Res. 29, 275–299 (1994).

    Article  CAS  PubMed  Google Scholar 

  113. Nusser, Z. et al. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21, 545–559 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Wilson, N. R. et al. Presynaptic regulation of quantal size by the vesicular glutamate transporter VGLUT1. J. Neurosci. 25, 6221–6234 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wu, X. S. et al. The origin of quantal size variation: vesicular glutamate concentration plays a significant role. J. Neurosci. 27, 3046–3056 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Conti, R. & Lisman, J. The high variance of AMPA receptor- and NMDA receptor-mediated responses at single hippocampal synapses: evidence for multiquantal release. Proc. Natl Acad. Sci. USA 100, 4885–4890 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Conti, R. & Lisman, J. A large sustained Ca2+ elevation occurs in unstimulated spines during the LTP pairing protocol but does not change synaptic strength. Hippocampus 12, 667–679 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Oertner, T. G., Sabatini, B. L., Nimchinsky, E. A. & Svoboda, K. Facilitation at single synapses probed with optical quantal analysis. Nature Neurosci. 5, 657–664 (2002). This paper uses two-photon calcium imaging to infer that multivesicular release can occur at single synapses.

    Article  CAS  PubMed  Google Scholar 

  119. Wadiche, J. I. & Jahr, C. E. Multivesicular release at climbing fiber–Purkinje cell synapses. Neuron 32, 301–313 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Foster, K. A., Kreitzer, A. C. & Regehr, W. G. Interaction of postsynaptic receptor saturation with presynaptic mechanisms produces a reliable synapse. Neuron 36, 1115–1126 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Christie, J. M. & Jahr, C. E. Multivesicular release at Schaffer collateral–CA1 hippocampal synapses. J. Neurosci. 26, 210–216 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Satzler, K. et al. Three-dimensional reconstruction of a calyx of Held and its postsynaptic principal neuron in the medial nucleus of the trapezoid body. J. Neurosci. 22, 10567–10579 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Biro, A. A., Holderith, N. B. & Nusser, Z. Quantal size is independent of the release probability at hippocampal excitatory synapses. J. Neurosci. 25, 223–232 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Stevens, C. F. & Wang, Y. Facilitation and depression at single central synapses. Neuron 14, 795–802 (1995).

    Article  CAS  PubMed  Google Scholar 

  125. Bolshakov, V. Y. & Siegelbaum, S. A. Regulation of hippocampal transmitter release during development and long-term potentiation. Science 269, 1730–1734 (1995).

    Article  CAS  PubMed  Google Scholar 

  126. Chen, G., Harata, N. C. & Tsien, R. W. Paired-pulse depression of unitary quantal amplitude at single hippocampal synapses. Proc. Natl Acad. Sci. USA 101, 1063–1068 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Silver, R. A., Lubke, J., Sakmann, B. & Feldmeyer, D. High-probability uniquantal transmission at excitatory synapses in barrel cortex. Science 302, 1981–1984 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Shapira, M. et al. Unitary assembly of presynaptic active zones from Piccolo-Bassoon transport vesicles. Neuron 38, 237–252 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Lisman, J. & Raghavachari, S. A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Science's STKE [online] (2006).

  130. Cathala, L., Holderith, N. B., Nusser, Z., DiGregorio, D. A. & Cull-Candy, S. G. Changes in synaptic structure underlie the developmental speeding of AMPA receptor-mediated EPSCs. Nature Neurosci. 8, 1310–1318 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Bolshakov, V. Y., Golan, H., Kandel, E. R. & Siegelbaum, S. A. Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3–CA1 synapses in the hippocampus. Neuron 19, 635–651 (1997).

    Article  CAS  PubMed  Google Scholar 

  132. Ostroff, L. E., Fiala, J. C., Allwardt, B. & Harris, K. M. Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron 35, 535–545 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Tsien, R. W., Ellinor, P. T. & Horne, W. A. Molecular diversity of voltage-dependent Ca2+ channels. Trends Pharmacol. Sci. 12, 349–354 (1991).

    Article  CAS  PubMed  Google Scholar 

  134. Catterall, W. A. Structure and function of voltage-gated sodium and calcium channels. Curr. Opin. Neurobiol. 1, 5–13 (1991).

    Article  CAS  PubMed  Google Scholar 

  135. Dunlap, K., Luebke, J. I. & Turner, T. J. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci. 18, 89–98 (1995).

    Article  CAS  PubMed  Google Scholar 

  136. Nowycky, M. C., Fox, A. P. & Tsien, R. W. Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316, 440–443 (1985).

    Article  CAS  PubMed  Google Scholar 

  137. Hirning, L. D. et al. Dominant role of N-type Ca2+ channels in evoked release of norepinephrine from sympathetic neurons. Science 239, 57–61 (1988).

    Article  CAS  PubMed  Google Scholar 

  138. Stanley, E. F. & Goping, G. Characterization of a calcium current in a vertebrate cholinergic presynaptic nerve terminal. J. Neurosci. 11, 985–993 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Stanley, E. F. Single calcium channels on a cholinergic presynaptic nerve terminal. Neuron 7, 585–591 (1991).

    Article  CAS  PubMed  Google Scholar 

  140. Llinás, R., Sugimori, M., Hillman, D. E. & Cherksey, B. Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system. Trends Neurosci. 15, 351–355 (1992).

    Article  PubMed  Google Scholar 

  141. Sather, W. A. et al. Distinctive biophysical and pharmacological properties of class A (BI) calcium channel α1 subunits. Neuron 11, 291–303 (1993).

    Article  CAS  PubMed  Google Scholar 

  142. Randall, A. & Tsien, R. W. Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J. Neurosci. 15, 2995–3012 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Takahashi, T. & Momiyama, A. Different types of calcium channels mediate central synaptic transmission. Nature 366, 156–158 (1993).

    Article  CAS  PubMed  Google Scholar 

  144. Luebke, J. I., Dunlap, K. & Turner, T. J. Multiple calcium channel types control glutamatergic synaptic transmission in the hippocampus. Neuron 11, 895–902 (1993).

    Article  CAS  PubMed  Google Scholar 

  145. Wheeler, D. B., Randall, A. & Tsien, R. W. Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264, 107–111 (1994).

    Article  CAS  PubMed  Google Scholar 

  146. Forsythe, I. D. Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS in vitro. J. Physiol. 479, 381–387 (1994).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Ertel, E. A. et al. Nomenclature of voltage-gated calcium channels. Neuron 25, 533–535 (2000).

    Article  CAS  PubMed  Google Scholar 

  148. Olivera, B. M., Miljanich, G. P., Ramachandran, J. & Adams, M. E. Calcium channel diversity and neurotransmitter release: the ω-conotoxins and ω-agatoxins. Annu. Rev. Biochem. 63, 823–867 (1994).

    Article  CAS  PubMed  Google Scholar 

  149. Campbell, K. P., Leung, A. T. & Sharp, A. H. The biochemistry and molecular biology of the dihydropyridine-sensitive calcium channel. Trends Neurosci. 11, 425–430 (1988).

    Article  CAS  PubMed  Google Scholar 

  150. Scholz, K. P. & Miller, R. J. Developmental changes in presynaptic calcium channels coupled to glutamate release in cultured rat hippocampal neurons. J. Neurosci. 15, 4612–4617 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Tsien, R. W., Hess, P., McCleskey, E. W. & Rosenberg, R. L. Calcium channels: mechanisms of selectivity, permeation, and block. Annu. Rev. Biophys. Biophys. Chem. 16, 265–290 (1987).

    Article  CAS  PubMed  Google Scholar 

  152. Sather, W. A. & McCleskey, E. W. Permeation and selectivity in calcium channels. Annu. Rev. Physiol. 65, 133–159 (2003).

    Article  CAS  PubMed  Google Scholar 

  153. Zhou, Y. D., Turner, T. J. & Dunlap, K. Enhanced G protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel-mutant mouse, tottering. J. Physiol. 547, 497–507 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Colecraft, H. M., Patil, P. G. & Yue, D. T. Differential occurrence of reluctant openings in G-protein-inhibited N- and P/Q-type calcium channels. J. Gen. Physiol. 115, 175–192 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Pietrobon, D. Calcium channels and channelopathies of the central nervous system. Mol. Neurobiol. 25, 31–50 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Miljanich, G. P. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem. 11, 3029–3040 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Choi, S., Klingauf, J. & Tsien, R. W. Postfusional regulation of cleft glutamate concentration during LTP at 'silent synapses'. Nature Neurosci. 3, 330–336 (2000).

    Article  CAS  PubMed  Google Scholar 

  158. Montgomery, J. M., Pavlidis, P. & Madison, D. V. Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation. Neuron 29, 691–701 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Renger, J. J., Egles, C. & Liu, G. A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation. Neuron 29, 469–484 (2001).

    Article  CAS  PubMed  Google Scholar 

  160. Krupa, B. & Liu, G. Does the fusion pore contribute to synaptic plasticity? Trends Neurosci. 27, 62–66 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Photowala, H., Blackmer, T., Schwartz, E., Hamm, H. E. & Alford, S. G protein βγ-subunits activated by serotonin mediate presynaptic inhibition by regulating vesicle fusion properties. Proc. Natl Acad. Sci. USA 103, 4281–4286 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zakharenko, S. S., Zablow, L. & Siegelbaum, S. A. Altered presynaptic vesicle release and cycling during mGluR-dependent LTD. Neuron 35, 1099–1110 (2002).

    Article  CAS  PubMed  Google Scholar 

  163. Nakagawa, T., Cheng, Y., Sheng, M. & Walz, T. Three-dimensional structure of an AMPA receptor without associated stargazin/TARP proteins. Biol. Chem. 387, 179–187 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Madden, D. R. The structure and function of glutamate receptor ion channels. Nature Rev. Neurosci. 3, 91–101 (2002).

    Article  CAS  Google Scholar 

  165. Armstrong, N., Sun, Y., Chen, G. Q. & Gouaux, E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395, 913–917 (1998).

    Article  CAS  PubMed  Google Scholar 

  166. Armstrong, N. & Gouaux, E. Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28, 165–181 (2000).

    Article  CAS  PubMed  Google Scholar 

  167. Sun, Y. et al. Mechanism of glutamate receptor desensitization. Nature 417, 245–253 (2002).

    Article  CAS  PubMed  Google Scholar 

  168. Armstrong, N., Jasti, J., Beich-Frandsen, M. & Gouaux, E. Measurement of conformational changes accompanying desensitization in an ionotropic glutamate receptor. Cell 127, 85–97 (2006). A structural study of AMPA channels that provides clear insight into the mechanism of desensitization.

    Article  CAS  PubMed  Google Scholar 

  169. Rosenmund, C., Stern-Bach, Y. & Stevens, C. F. The tetrameric structure of a glutamate receptor channel. Science 280, 1596–1599 (1998). An important paper demonstrating the tetrameric structure of AMPA channels and the fact that different channel occupancy by glutamate leads to different single-channel conductance.

    Article  CAS  PubMed  Google Scholar 

  170. Smith, T. C. & Howe, J. R. Concentration-dependent substate behavior of native AMPA receptors. Nature Neurosci. 3, 992–997 (2000).

    Article  CAS  PubMed  Google Scholar 

  171. Ruiz, M. & Karpen, J. W. Opening mechanism of a cyclic nucleotide-gated channel based on analysis of single channels locked in each liganded state. J. Gen. Physiol. 113, 873–895 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ruiz, M. L. & Karpen, J. W. Single cyclic nucleotide-gated channels locked in different ligand-bound states. Nature 389, 389–392 (1997).

    Article  CAS  PubMed  Google Scholar 

  173. Raman, I. M. & Trussell, L. O. The mechanism of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor desensitization after removal of glutamate. Biophys. J. 68, 137–146 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Hausser, M. & Roth, A. Estimating the time course of the excitatory synaptic conductance in neocortical pyramidal cells using a novel voltage jump method. J. Neurosci. 17, 7606–7625 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Diamond, J. S. & Jahr, C. E. Transporters buffer synaptically released glutamate on a submillisecond time scale. J. Neurosci. 17, 4672–4687 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Postlethwaite, M., Hennig, M. H., Steinert, J. R., Graham, B. P. & Forsythe, I. D. Acceleration of AMPA receptor kinetics underlies temperature-dependent changes in synaptic strength at the rat calyx of Held. J. Physiol. 579, 69–84 (2007).

    Article  CAS  PubMed  Google Scholar 

  177. Robert, A. & Howe, J. R. How AMPA receptor desensitization depends on receptor occupancy. J. Neurosci. 23, 847–858 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Rostaing, P. et al. Analysis of synaptic ultrastructure without fixative using high-pressure freezing and tomography. Eur. J. Neurosci. 24, 3463–3474 (2006).

    Article  PubMed  Google Scholar 

  179. Siksou, L. et al. Three-dimensional architecture of presynaptic terminal cytomatrix. J. Neurosci. 27, 6868–6877 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank M. Jackson, J. Zimmerberg, A. Silver, S. Marty, L.-G. Wu, Z. Nusser, R. Schneggenburger, G. Fain and E. Marder for useful discussions. J.E.L. has been supported by the US National Institutes of Health (NIH) grants R01 NS27337 and R01 NS50944 as part of the Collaborative Research in Computational Neuroscience Program. R.W.T. has been supported by NIH grants NS24067 and MH64070 and generous support from the Mathers Foundation. S.R. has been supported by the National Science Foundation grant 0642000.

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Authors and Affiliations

  1. Department of Biology, Brandeis University, MS 008, 415 South Street, Waltham, 02454-9110, Massachusetts, USA

    John E. Lisman

  2. Department of Neurobiology, Duke University, Box 3209, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Sridhar Raghavachari

  3. Department of Molecular & Cellular Physiology, Stanford University School of Medicine, Beckman Center, Room B100, 279 Campus Drive, Stanford, 94305-5345, California, USA

    Richard W. Tsien

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Synapse Web

Glossary

Synapse

The term synapse can be used either in a structural sense or to describe an entire connection. According to the structural definition, a synapse consists of a single presynaptic active zone and postsynaptic density, together with the specialized membranes and cleft in-between. Synapse diameter is between 0.2 and 1 micron. At most dendritic spines, there is a single such synapse. Giant synaptic connections have many structural synapses; the mossy fibre boutons in CA3 have over 10, whereas the Calyx of Held has approximately 50.

Quanta

The elementary building block of the EPSC, which contains an integral number of these events. Quantal size is derived from the distance between the peaks in the amplitude histogram of the EPSC, and equals the amplitude of the mEPSC at synapses where these events are uniquantal.

Fusion pore

Provides the passage from the interior of the vesicle into the synaptic cleft, through which neurotransmitter diffuses.

Excitatory postsynaptic current

(EPSC). The inward postsynaptic membrane current evoked by a single presynaptic action potential. It is measured using the voltage-clamp technique.

Electrochemical driving force

The difference between the Nernst equilibrium potential for an ion and the membrane voltage. The current through a channel is the product of the channel conductance and the electrochemical driving force.

Uncaging methods

The standard form of a compound is modified by chemical adducts, which can be cleaved by bright light to produce the standard form. One application of this technology allows rapid light-induced Ca2+ elevation.

Release site

A site in the active zone where the vesicle is released. It remains unclear whether there is a structural basis for such sites, or whether release can occur anywhere in the active zone provided that the appropriate vesicle priming has occurred.

Impedance method

A rapidly oscillating voltage is applied by voltage-clamp. The in-phase component of the resulting current is termed the 'real' component and can be related to patch conductance. The out-of-phase component is called the imaginary component and can be related to patch capacitance. The advantage of this method is that both conductance and capacitance can be measured simultaneously.

Monte-Carlo simulation

A simulation that involves keeping track of the position and state of each molecule. At each short time step the computer calculates the new position or state of each molecule according to the probability of each change.

Kinetic model

The kinetic model of an ion channel specifies the rate constants for the binding and unbinding of neurotransmitter to sites on the channel, and the rate of conformational transitions between various states that control channel opening and closing, as well as transitions to a desensitized state.

mEPSC

(miniature EPSC). An mEPSC is a spontaneously occurring synaptic event caused by spontaneous vesicle release. It is generally measured after blocking action potentials with tetrodotoxin to insure that there is no release due to spontaneous action potentials. The amplitude of mEPSCs is determined by AMPA channel density and is taken as a measure of postsynaptic processes in traditional quantal analysis. However, mEPSC amplitude can also be affected by vesicle glutamate concentration, multi-vesicular release and glutamate release mode.

Outside-out patch

A variant of the patch-clamp technique, in which a patch of plasma membrane covers the tip of the electrode. The outside of the membrane is exposed to bathing solution.

Coefficient of variation

(CV). The standard deviation divided by the mean. The CV is thus a convenient measure of the relative variability of a quantity. For instance, a CV of 0.2 would mean that most measurements were within plus or minus 20% of the mean.

Amplitude histogram

An amplitude histogram of the EPSC is made by defining amplitude bins and then plotting the number of occurrences that fall within each bin as a function of amplitude. For responses comprising a variable number of elementary quantal units, the histogram should show multiple peaks at integral multiples of quantal size. In practice, the peaks become smeared because of the CV of quantal size and because of measurement noise.

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Lisman, J., Raghavachari, S. & Tsien, R. The sequence of events that underlie quantal transmission at central glutamatergic synapses. Nat Rev Neurosci 8, 597–609 (2007). https://doi.org/10.1038/nrn2191

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