Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Diversification of synaptic strength: presynaptic elements

Nature Reviews Neuroscience volume 3, pages 497–516 (2002)Cite this article

Key Points

  • Synapses are functionally diverse. For example, synaptic strength can differ markedly from one synapse to the next. How does this diversity arise? What are its underlying mechanisms? Both structural and molecular explanations have been put forward to account for synaptic differentiation.

  • It is possible to define two general cases of synaptic functional differentiation. In case I, different branches of the same neuron evoke synaptic responses of diverse character in various follower cells. It is thought that retrograde influences from the follower cells determine synaptic properties. In case II, different presynaptic neurons that supply the same follower cell evoke different postsynaptic responses. In this case, upstream determination of presynaptic properties seems to be more significant.

  • From a presynaptic perspective, how could synaptic structure modify synaptic strength? There are several possibilities. Specifically, there might be presynaptic differences in the number of active zones per synapse, the density of Ca2+ channels in the active zone, the size of synaptic vesicles, the spacing between vesicles and Ca2+ channels, and the number of readily releasable vesicles. There is evidence for the contribution of each of these factors to synaptic differentiation of both invertebrate and vertebrate synapses.

  • Although quantal size has been thought to depend largely on postsynaptic factors, several presynaptic factors might also affect this variable. They include variations in the size of vesicles, in the intravesicular transmitter concentration or in the properties of the fusion event. However, the contribution of differences in quantal size to synaptic diversity under normal circumstances is not fully understood.

  • The size of the readily releasable vesicle pool also contributes to differences in synaptic strength. There is a linear relationship between docked and readily releasable vesicles, and the readily releasable pool size is tightly linked to release probability and to synapse size. These relationships have been best established for synapses in culture; although they have been postulated to apply also to synapses in vivo, their validity remains to be tested.

  • The number of synaptic Ca2+ channels and the type of channel might also affect synaptic strength. However, evidence for such a link is, at best, suggestive, as crucial physiological experiments that show a causal relationship in situ are still lacking.

  • Differences in vesicle–channel spacing and intracellular Ca2+ buffers might also contribute to differences in synaptic strength. Their effects are also tightly linked to the structure of the active zone, which has been the subject of recent debate. There is evidence that, at some synapses, the disposition of the vesicles and the Ca2+ channels is quite regular. However, it is not clear that such an arrangement is found at other synapses, and there is some evidence that it is not.

  • Synaptic structural features cannot account fully for differences in synaptic strength. So, underlying molecular differences must make an important contribution. How well can the known molecular candidates explain synaptic differentiation? To participate in differentiation, the candidate molecules need to co-localize with the synaptic difference, their disturbance must affect synaptic differentiation, and there should be proof that they contribute to differentiation in vivo. Although there are many molecular candidates, the evidence for their contribution to normally occurring synaptic differentiation is so far incomplete.

  • Although we have started to link physiological properties with molecular and structural substrates, little progress has been made in matching these features. An important goal for future research will be to decipher more of the molecular and structural rules that govern the expression of physiological phenotypes. The structural approach has been the most successful so far, as it has produced some general principles of variations in synaptic strength. By contrast, closing the loop between molecular and physiological differentiation remains the greatest challenge for this field.

Abstract

Synapses are not static; their performance is modified adaptively in response to activity. Presynaptic mechanisms that affect the probability of transmitter release or the amount of transmitter that is released are important in synaptic diversification. Here, we address the diversity of presynaptic performance and its underlying mechanisms: how much of the variation can be accounted for by variation in synaptic morphology and how much by molecular differences? Significant progress has been made in defining presynaptic structural contributions to synaptic strength; by contrast, we know little about how presynaptic proteins produce normally observed functional differentiation, despite abundant information on presynaptic proteins and on the effects of their individual manipulation. Closing the gap between molecular and physiological synaptic diversification still represents a considerable challenge.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Synaptic functional differentiation, case I: differences in the responses of a target cell to a single presynaptic neuron.
Figure 2: Synaptic functional differentiation, case II: responses evoked in a single target cell by different presynaptic inputs.
Figure 3: Presynaptic determinants of synaptic strength.
Figure 4: Quantal size and variance: evidence for presynaptic influence.
Figure 5: Synaptic vesicle pools and the putative contribution of readily releasable vesicles to synaptic strength.
Figure 6: Active zone structure.
Figure 7: Differential effects of Ca2+ buffers in mammalian central neurons.
Figure 8: Possible mechanisms that lead to differential synaptic strength.

Similar content being viewed by others

References

  1. del Castillo, J. & Katz, B. Quantal components of the end-plate potential. J. Physiol. (Lond.) 124, 560–573 (1954).

    CAS  Google Scholar 

  2. Fatt, P. & Katz, B. Spontaneous subthreshold activity at motor nerve endings. J. Physiol. (Lond.) 117, 109–128 (1952).

    CAS  Google Scholar 

  3. Katz, B. & Miledi, R. A study of synaptic transmission in the absence of nerve impulses. J. Physiol. (Lond.) 192, 407–436 (1967).

    CAS  PubMed Central  Google Scholar 

  4. Takeuchi, A. & Takeuchi, N. The effect on crayfish muscle of iontophoretically applied glutamate. J. Physiol. (Lond.) 170, 296–317 (1964).

    CAS  Google Scholar 

  5. Dudel, J. & Kuffler, S. W. Presynaptic inhibition at the crayfish neuromuscular junction. J. Physiol. (Lond.) 155, 543–562 (1961).

    CAS  Google Scholar 

  6. Atwood, H. L. & Wojtowicz, J. M. Short-term and long-term plasticity and physiological differentiation of crustacean motor synapses. Int. Rev. Neurobiol. 28, 275–362 (1986).

    CAS  PubMed  Google Scholar 

  7. Auerbach, A. A. & Bennett, M. V. L. Chemically mediated transmission at a giant fiber synapse in the central nervous system of a vertebrate. J. Gen. Physiol. 53, 183–210 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wickelgren, W. O. Physiological and anatomical characteristics of reticulospinal neurones in lamprey. J. Physiol. (Lond.) 270, 89–114 (1977).

    CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Forsythe, I. D. Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS, in vitro. J. Physiol. (Lond.) 479, 381–388 (1994).

    Google Scholar 

  11. Markram, H., Pikus, D., Gupta, A. & Tsodyks, M. Potential for multiple mechanisms, phenomena and algorithms for synaptic plasticity at single synapses. Neuropharmacology 37, 489–500 (1998).Presents the case for diversification at the single-synapse level in the mammalian CNS, claiming that each synaptic connection might have unique properties.

    CAS  PubMed  Google Scholar 

  12. Wiersma, C. A. G. in The Physiology of Crustacea Vol. 2 (ed. Waterman, T. H.) 191–240 (Academic, New York, 1961).

    Google Scholar 

  13. Korn, H. in Central Synapses: Quantal Mechanisms and Plasticity (eds Faber, D. S., Korn, H., Redman, S. J., Thompson, S. M. & Altman, J. S.) 19–23 (Human Frontier Science Program, Strasbourg, France, 1998).

    Google Scholar 

  14. Korn, H., Mallet, A., Triller, A. & Faber, D. S. Transmission at a central inhibitory synapse. II. Quantal description of release, with a physical correlate for binomial n. J. Neurophysiol. 48, 679–707 (1982).

    CAS  PubMed  Google Scholar 

  15. Bliss, T. V. P. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. (Lond.) 232, 331–356 (1973).

    CAS  Google Scholar 

  16. Thomson, A. M. Molecular frequency filters at central synapses. Prog. Neurobiol. 62, 159–196 (2000).

    CAS  PubMed  Google Scholar 

  17. Hoyle, G. & Wiersma, C. A. G. Excitation at neuromuscular junctions in crustacea. J. Physiol. (Lond.) 143, 403–425 (1958).

    CAS  Google Scholar 

  18. Bittner, G. D. Differentiation of nerve terminals in the crayfish opener muscle and its functional significance. J. Gen. Physiol. 51, 731–758 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sherman, R. G. & Atwood, H. L. Correlated electrophysiological and ultrastructural studies of a crustacean motor unit. J. Gen. Physiol. 59, 586–615 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Frank, E. Matching of facilitation at the neuromuscular junction of the lobster: a possible case for influence of muscle on nerve. J. Physiol. (Lond.) 233, 635–658 (1973).Introduces the case for a retrograde influence of target cells on synapses, with a clear-cut example from crustacean neuromuscular physiology.

    CAS  Google Scholar 

  21. Davis, G. W. & Murphey, R. K. Long-term regulation of short-term transmitter release properties: retrograde signaling and synaptic development. Trends Neurosci. 17, 9–13 (1994).

    CAS  PubMed  Google Scholar 

  22. Scanziani, M., Gähwiler, B. H. & Charpak, S. Target cell-specific modulation of transmitter release at terminals from a single axon. Proc. Natl Acad. Sci. USA 95, 12004–12009 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lnenicka, G. A. & Mellon, D. Transmitter release during normal and altered growth of identified muscle fibres in the crayfish. J. Physiol. (Lond.) 345, 285–296 (1983).

    CAS  Google Scholar 

  24. Davis, G. W. & Goodman, C. S. Synapse-specific control of synaptic efficacy at the terminals of a single neuron. Nature 392, 82–86 (1998).

    CAS  PubMed  Google Scholar 

  25. Davis, G. W., DiAntonio, A., Petersen, S. A. & Goodman, C. S. Postsynaptic PKA controls quantal size and reveals a retrograde signal that regulates presynaptic transmitter release in Drosophila. Neuron 20, 305–315 (1998).

    CAS  PubMed  Google Scholar 

  26. Feng, Z. P. et al. Development of Ca2+ hotspots between Lymnaea neurons during synaptogenesis. J. Physiol. (Lond.) 539, 53–65 (2002).

    CAS  Google Scholar 

  27. Kennedy, D. & Takeda, K. Reflex control of abdominal flexor muscles in the crayfish. I. The twitch system. J. Exp. Biol. 43, 211–227 (1965).

    Google Scholar 

  28. Markram, H., Gupta, A., Uziel, A., Wang, Y. & Tsodyks, M. Information processing with frequency-dependent synaptic connections. Neurobiol. Learn. Mem. 70, 101–112 (1998).

    CAS  PubMed  Google Scholar 

  29. Gupta, A., Wang, Y. & Markram, H. Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 287, 273–278 (2000).

    CAS  PubMed  Google Scholar 

  30. Malgaroli, A. in Central Synapses: Quantal Mechanisms and Plasticity (eds Faber, D. S., Korn, H., Redman, S. J., Thompson, S. M. & Altman, J. S.) 123–130 (Human Frontier Science Program, Strasbourg, France, 1998).

    Google Scholar 

  31. Murthy, V. N., Sejnowski, T. J. & Stevens, C. F. Heterogeneous release properties of visualized individual hippocampal synapses. Neuron 18, 599–612 (1997).

    CAS  PubMed  Google Scholar 

  32. Murphy, T. H., Baraban, J. M., Wier, W. G. & Blatter, L. A. Visualisation of quantal synaptic transmission by dendritic calcium imaging. Science 263, 529–532 (1994).References 31 and 32 used optical methods to analyse synaptic transmission, and revealed heterogeneous release properties of synapses in tissue culture.

    CAS  PubMed  Google Scholar 

  33. Atwood, H. L. & Wojtowicz, J. M. Silent synapses in neural plasticity: current evidence. Learn. Mem. 6, 542–571 (1999).

    CAS  PubMed  Google Scholar 

  34. Chen, C. F., Blitz, D. M. & Regehr, W. G. Contributions of receptor desensitization and saturation to plasticity at the retinogeniculate synapse. Neuron 33, 779–788 (2002).

    CAS  PubMed  Google Scholar 

  35. Llinás, R. R. in Approaches to the Cell Biology of Neurons (eds Cowan, W. M. & Ferendelli, J. A.) 139–160 (Society for Neuroscience, Bethesda, Maryland, 1977).

    Google Scholar 

  36. Sabatini, B. L. & Regehr, W. G. Control of neurotransmitter release by presynaptic waveform at the granule cell to Purkinje cell synapse. J. Neurosci. 17, 3425–3435 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Geiger, J. R. P. & Jonas, P. Dynamic control of presynaptic Ca2+ inflow by fast-inactivating K+ channels in hippocampal mossy fiber boutons. Neuron 28, 927–939 (2000).The importance of the presynaptic action potential waveform for transmission in the mammalian CNS is presented in references 36 and 37.

    CAS  PubMed  Google Scholar 

  38. Wang, L.-Y. & Kaczmarek, L. K. High-frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature 394, 384–388 (1998).

    CAS  PubMed  Google Scholar 

  39. Lu, W. et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001).

    CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. Auger, C. & Marty, A. Quantal currents at single-site central synapses. J. Physiol. (Lond.) 526, 3–11 (2000).

    CAS  Google Scholar 

  42. Harris, K. M. & Sultan, P. Variation in the number, location and size of synaptic vesicles provides an anatomical basis for the nonuniform probability of release at hippocampal CA1 synapses. Neuropharmacology 34, 1387–1395 (1995).

    CAS  PubMed  Google Scholar 

  43. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Faber, D. S., Young, W. S., Legendre, P. & Korn, H. Intrinsic quantal variability due to stochastic properties of receptor–transmitter interactions. Science 258, 1494–1498 (1992).

    CAS  PubMed  Google Scholar 

  45. Frerking, M. & Wilson, M. Saturation of postsynaptic receptors at central synapses. Curr. Opin. Neurobiol. 6, 395–403 (1996).

    CAS  PubMed  Google Scholar 

  46. Liu, G. S., Choi, S. W. & 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).

    CAS  PubMed  Google Scholar 

  47. Ishikawa, T., Sahara, Y. & Takahashi, T. A single packet of transmitter does not saturate postsynaptic glutamate receptors. Neuron 34, 613–621 (2002).References 46 and 47 present evidence for non-saturation of postsynaptic receptors by a quantal event.

    CAS  PubMed  Google Scholar 

  48. Frerking, M., Borges, S. & Wilson, M. Variation in GABA mini amplitude is the consequence of variation in transmitter concentration. Neuron 15, 885–895 (1995).Variation in transmitter content of vesicles determines the variation in quantal amplitude.

    CAS  PubMed  Google Scholar 

  49. Colliver, T. L., Pyott, S. J., Achalabun, M. & Ewing, A. G. VMAT-mediated changes in quantal size and vesicular volume. J. Neurosci. 20, 5276–5282 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Bruns, D., Riedel, D., Klingauf, J. & Jahn, R. Quantal release of serotonin. Neuron 28, 205–220 (2000).

    CAS  PubMed  Google Scholar 

  51. Henze, D. A., McMahon, D. B. T., Harris, K. M. & Barrionuevo, G. Giant miniature EPSCs at the hippocampal mossy fiber to CA3 pyramidal cell synapse are monoquantal. J. Neurophysiol. 87, 15–29 (2002).

    PubMed  Google Scholar 

  52. Zhang, B. et al. Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis. Neuron 21, 1465–1475 (1998).The relationship between synaptic vesicle volume and quantal amplitude is shown by a genetic approach.

    CAS  PubMed  Google Scholar 

  53. Fergestad, T., Davis, W. S. & Broadie, K. The stoned proteins regulate synaptic vesicle recycling in the presynaptic terminal. J. Neurosci. 19, 5847–5860 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Song, H. J. et al. Expression of a putative vesicular acetylcholine transporter facilitates quantal transmitter packaging. Neuron 18, 815–826 (1997).

    CAS  PubMed  Google Scholar 

  55. Engel, D. et al. Plasticity of rat central inhibitory synapses through GABA metabolism. J. Physiol. (Lond.) 535, 473–482 (2001).Metabolic regulation of quantal size (more transmitter in a quantal unit) is shown for inhibitory synapses.

    CAS  Google Scholar 

  56. Klingauf, J., Kavalali, E. T. & Tsien, R. W. Kinetics and regulation of fast endocytosis at hippocampal synapses. Nature 394, 581–585 (1998).

    CAS  PubMed  Google Scholar 

  57. Stevens, C. F. & Williams, J. H. 'Kiss and run' exocytosis at hippocampal synapses. Proc. Natl Acad. Sci. USA 97, 12828–12833 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Maler, L. & Mathieson, W. B. The effect of nerve activity on the distribution of synaptic vesicles. Cell. Mol. Neurobiol. 5, 373–387 (1985).

    CAS  PubMed  Google Scholar 

  59. Wickelgren, W. O., Leonard, J. P., Grimes, M. J. & Clark, R. D. Ultrastructural correlates of transmitter release in presynaptic areas of lamprey reticulospinal axons. J. Neurosci. 5, 1188–1201 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Zimmermann, H. & Whittaker, V. P. Effect of electrical stimulation on the yield and composition of synaptic vesicles from the cholinergic synapses of the electric organ of Torpedo: a combined biochemical, electrophysiological and morphological study. J. Neurochem. 22, 435–450 (1974).

    CAS  PubMed  Google Scholar 

  61. Naves, L. A. & Van der Kloot, W. Repetitive nerve stimulation decreases the acetylcholine content of quanta at the frog neuromuscular junction. J. Physiol. (Lond.) 532, 637–647 (2001).

    CAS  Google Scholar 

  62. Atwood, H. L., Lang, F. & Morin, W. A. Synaptic vesicles: selective depletion in crayfish excitatory and inhibitory axons. Science 176, 1353–1355 (1972).

    CAS  PubMed  Google Scholar 

  63. Koenig, J. H. & Ikeda, K. Disappearance and reformation of synaptic vesicle membrane upon transmitter release observed under reversible blockage of membrane retrieval. J. Neurosci. 9, 3844–3860 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Heuser, J. E., Reese, T. S. & Landis, D. M. D. Functional changes in frog neuromuscular junctions studied with freeze-fracture. J. Neurocytol. 3, 109–131 (1974).

    CAS  PubMed  Google Scholar 

  65. Murthy, V. N. & Stevens, C. F. Synaptic vesicles retain their identity through the endocytic cycle. Nature 392, 497–501 (1998).

    CAS  PubMed  Google Scholar 

  66. Harata, N. et al. Limited numbers of recycling vesicles in small CNS nerve terminals: implications for neural signaling and vesicular cycling. Trends Neurosci. 24, 637–643 (2001).References 65 and 66 make the case for limited numbers of recycling synaptic vesicles in a presynaptic bouton of mammalian neurons in culture.

    CAS  PubMed  Google Scholar 

  67. Zenisek, D., Steyer, J. A. & Almers, W. Transport, capture and exocytosis of single synaptic vesicles at active zones. Nature 406, 849–854 (2000).

    CAS  PubMed  Google Scholar 

  68. Harata, N., Ryan, T. A., Smith, S. J., Buchanan, J. & Tsien, R. W. Visualizing recycling synaptic vesicles in hippocampal neurons by FM1-43 photoconversion. Proc. Natl Acad. Sci. USA 98, 12748–12753 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Schikorski, T. & Stevens, C. F. Morphological correlates of functionally defined synaptic vesicle populations. Nature Neurosci. 4, 391–395 (2001).

    CAS  PubMed  Google Scholar 

  70. Dobrunz, L. E. & Stevens, C. F. Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron 18, 995–1008 (1997).

    CAS  PubMed  Google Scholar 

  71. Murthy, V. N., Schikorski, T., Stevens, C. F. & Zhu, Y. Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32, 673–682 (2001).The relationships between release probability, synapse size and readily releasable vesicles in cultured mammalian neurons are developed in references 69–71 . Readily releasable vesicle pool size is directly correlated with release probability.

    CAS  PubMed  Google Scholar 

  72. Hanse, E. & Gustafsson, B. Factors explaining heterogeneity in short-term synaptic dynamics of hippocampal glutamatergic synapses in the neonatal rat. J. Physiol. (Lond.) 537, 141–149 (2001).An analysis of synaptic physiological variation in mammalian brain slices, claiming some differences between synapses of slices and cultures.

    CAS  Google Scholar 

  73. Xu-Friedman, M. A., Harris, K. M. & Regehr, W. G. Three-dimensional comparison of ultrastructural characteristics at depressing and facilitating synapses onto cerebellar Purkinje cells. J. Neurosci. 21, 6666–6672 (2001).This ultrastructural study makes the point that docked vesicle numbers cannot explain the physiological differences between two inputs to the same target neuron in the cerebellum.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Schneggenburger, R., Meyer, A. C. & Neher, E. Released fraction and total size of a pool of immediately available transmitter quanta at a calyx synapse. Neuron 23, 399–409 (1999).

    CAS  PubMed  Google Scholar 

  75. Millar, A. G., Hua, S. Y., Marin, L., Charlton, M. P. & Atwood, H. L. Immediately releasable vesicles and released fractions at phasic and tonic synapses. Soc. Neurosci. Abstr. 27, 384.3 (2001).

    Google Scholar 

  76. Atwood, H. L. & Jahromi, S. S. Fast-axon synapses in crab leg muscle. J. Neurobiol. 9, 1–15 (1978).

    CAS  PubMed  Google Scholar 

  77. Couteaux, R. Vesicles synaptiques et poches au niveau des 'zones active' de la junction neuromusculaire. C R Seances Acad. Sci. D 271, 2346–2349 (1970).

    CAS  Google Scholar 

  78. Walrond, J. P. & Reese, T. S. Structure of axon terminals and active zones at synapses on lizard twitch and tonic muscle fibers. J. Neurosci. 5, 1118–1131 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Parsegian, V. A. in Approaches to the Cell Biology of Neurons (eds Cowan, W. W. & Ferrendelli, J. A.) 161–171 (Society for Neuroscience, Bethesda, Maryland, 1977).

    Google Scholar 

  80. Robitaille, R., Adler, E. M. & Charlton, M. P. Strategic location of calcium channels at transmitter release sites of frog neuromuscular synapses. Neuron 5, 773–779 (1990).

    CAS  PubMed  Google Scholar 

  81. Haydon, P. G., Henderson, E. & Stanley, E. F. Localization of individual calcium channels at the release face of a presynaptic nerve terminal. Neuron 13, 1275–1280 (1994).References 80 and 81 provide immunocytochemical and ultrastructural evidence for the localization of presynaptic Ca2+ channels at active zones.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  83. Ahmari, S. E., Buchanan, J. & Smith, S. J. Assembly of presynaptic active zones from cytoplasmic transport packets. Nature Neurosci. 3, 445–451 (2000).

    CAS  PubMed  Google Scholar 

  84. Nicol, M. J. & Walmsley, B. Ultrastructural basis of synaptic transmission between endbulbs of Held and bushy cells in the rat cochlear nucleus. J. Physiol. (Lond.) 539, 713–723 (2002).

    CAS  Google Scholar 

  85. Meinrenken, C. J., Borst, J. G. G. & Sakmann, B. Calcium secretion coupling at calyx of Held governed by nonuniform channel–vesicle topography. J. Neurosci. 22, 1648–1667 (2002).This theoretical study develops the case for non-uniformity of vesicle–Ca2+ channel spacing in the calyx of Held.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Sheng, Z. H., Westenbroek, R. E. & Catterall, W. A. Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking/fusion machinery. J. Bioenerg. Biomembr. 30, 335–345 (1998).

    CAS  PubMed  Google Scholar 

  87. Bennett, M. R., Lavidis, N. A. & Lavidis-Armson, F. The probability of quantal secretion at release sites of different length in toad (Bufo marinus) muscle. J. Physiol. (Lond.) 418, 235–249 (1989).

    CAS  Google Scholar 

  88. Cooper, R. L., Harrington, C. C., Marin, L. & Atwood, H. L. Quantal release at visualized terminals of a crayfish motor axon: intraterminal and regional differences. J. Comp. Neurol. 375, 583–600 (1996).

    CAS  PubMed  Google Scholar 

  89. Cooper, R. L., Marin, L. & Atwood, H. L. Synaptic differentiation of a single motor neuron: conjoint definition of transmitter release, presynaptic calcium signals, and ultrastructure. J. Neurosci. 15, 4209–4222 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Msghina, M., Millar, A. G., Charlton, M. P., Govind, C. K. & Atwood, H. L. Calcium entry related to active zones and differences in transmitter release at phasic and tonic synapses. J. Neurosci. 19, 8419–8434 (1999).For crustacean synapses, Ca2+ entry per active zone cannot explain the difference in transmitter release between phasic and tonic synapses.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Fisher, T. E. & Bourque, C. W. The function of Ca2+ channel subtypes in exocytotic secretion: new perspectives from synaptic and non-synaptic release. Prog. Biophys. Mol. Biol. 77, 269–303 (2001).

    CAS  PubMed  Google Scholar 

  92. Jarvis, S. E. & Zamponi, G. W. Interactions between presynaptic Ca2+ channels, cytoplasmic messengers and proteins of the synaptic vesicle release complex. Trends Pharmacol. Sci. 22, 519–525 (2001).

    CAS  PubMed  Google Scholar 

  93. Moreno Davila, H. Molecular and functional diversity of voltage-gated calcium channels. Ann. NY Acad. Sci. 868, 102–117 (1999).

    CAS  PubMed  Google Scholar 

  94. Stotz, S. C. & Zamponi, G. W. Structural determinants of fast inactivation of high voltage-activated Ca2+ channels. Trends Neurosci. 24, 176–181 (2001).

    CAS  PubMed  Google Scholar 

  95. Ludwig, A., Flockerzi, V. & Hofmann, F. Regional expression and cellular localization of the α1 and β subunit of high voltage-activated calcium channels in rat brain. J. Neurosci. 17, 1339–1349 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang, J. H., Lai, Z. & Simonds, W. F. Differential expression of the G protein β5 gene: analysis of mouse brain, peripheral tissues, and cultured cell lines. J. Neurochem. 75, 393–403 (2000).

    CAS  PubMed  Google Scholar 

  97. Reid, C. A., Clements, J. A. & Bekkers, J. M. Nonuniform distribution of Ca2+ channel subtypes on presynaptic terminals of excitatory synapses in hippocampal cultures. J. Neurosci. 17, 2738–2745 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Reid, C. A., Bekkers, J. M. & Clements, J. D. N- and P/Q-type Ca2+ channels mediate transmitter release with a similar cooperativity at rat hippocampal autapses. J. Neurosci. 18, 2849–2855 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Rathmayer, W., Djokaj, S., Gaydukov, A. & Kreissl, S. The neuromuscular junctions of the slow and the fast excitatory axon in the closer of the crab Eriphia spinifrons are endowed with different Ca2+ channel types and allow neuron-specific modulation of transmitter release by two neuropeptides. J. Neurosci. 22, 708–717 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Wu, L. G., Westenbroek, R. E., Borst, J. G. 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).Differential localization of Ca2+ channel types at active zones can account for their relative effectiveness in releasing transmitter.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Stanley, E. F. Single calcium channels and acetylcholine release at a presynaptic nerve terminal. Neuron 11, 1007–1011 (1993).Evidence that a synaptic vesicle can fuse by the opening of a single N-type Ca2+ channel in the calyciform synapse of the chick ciliary ganglion.

    CAS  PubMed  Google Scholar 

  102. Mansvelder, H. D. & Kits, K. S. All classes of calcium channel couple with equal efficiency to exocytosis in rat melanotropes, inducing linear stimulus–secretion coupling. J. Physiol. (Lond.) 526, 327–339 (2000).

    CAS  Google Scholar 

  103. Westenbroek, R. E. et al. Immunochemical identification and subcellular distribution of the α1A subunits of brain calcium channels. J. Neurosci. 15, 6403–6418 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Rettig, J. et al. Isoform-specific interaction of the α1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proc. Natl Acad. Sci. USA 93, 7363–7368 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Catterall, W. A. Structure and function of voltage-gated ion channels. Annu. Rev. Biochem. 64, 493–531 (1995).

    CAS  PubMed  Google Scholar 

  106. Simon, S. M. & Llinas, R. R. Compartmentalization of the submembrane calcium activity during calcium influx and its significance in transmitter release. Biophys. J. 48, 485–498 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Sugimori, M., Lang, E. J., Silver, R. B. & Llinás, R. High-resolution measurement of the time course of calcium-concentration microdomains at squid presynaptic terminals. Biol. Bull. 187, 300–303 (1994).

    CAS  PubMed  Google Scholar 

  108. Tucker, T. & Fettiplace, R. Confocal imaging of calcium microdomains and calcium extrusion in turtle hair cells. Neuron 15, 1323–1335 (1995).

    CAS  PubMed  Google Scholar 

  109. DiGregorio, D. A. & Vergara, J. L. Localized detection of action potential-induced presynaptic calcium transients at a Xenopus neuromuscular junction. J. Physiol. (Lond.) 505, 585–592 (1997).Highly resolved observation of Ca2+ transients at active zones of the amphibian NMJ.

    CAS  Google Scholar 

  110. Tank, D. W., Regehr, W. G. & Delaney, K. R. A quantitative analysis of presynaptic calcium dynamics that contribute to short-term enhancement. J. Neurosci. 15, 7940–7952 (1995).Presents the single-compartment model of Ca2+ signals in individual boutons.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Klingauf, J. & Neher, E. Modeling buffered Ca2+ diffusion near the membrane: implications for secretion in neuroendocrine cells. Biophys. J. 72, 674–690 (1997).Models the influence of intracellular buffers on Ca2+ diffusion near points of entry.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Fogelson, A. L. & Zucker, R. S. Presynaptic calcium diffusion from various arrays of single channels. Biophys. J. 48, 1003–1017 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Bennett, M. R., Farnell, L. & Gibson, W. G. The probability of quantal secretion within an array of calcium channels of an active zone. Biophys. J. 78, 2222–2240 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Bertram, R., Smith, G. D. & Sherman, A. Modeling study of the effects of overlapping Ca2+ microdomains on neurotransmitter release. Biophys. J. 76, 735–750 (1999).References 113 and 114 present models of the influence of Ca2+ on exocytosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Stern, M. D. Buffering of calcium in the vicinity of a channel pore. Cell Calcium 13, 183–192 (1992).

    CAS  PubMed  Google Scholar 

  116. Xu, T., Naraghi, M., Kang, H. & Neher, E. Kinetic studies of Ca2+ clearance in the cytosol of adrenal chromaffin cells. Biophys. J. 73, 532–545 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Adler, E. M., Augustine, G. J., Duffy, S. N. & Charlton, M. P. Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse. J. Neurosci. 11, 1496–1507 (1991).The first examination of the effects of introduced Ca2+ buffers on transmission. 'Slow' buffers were ineffective at the squid giant synapse, whereas 'fast' buffers were effective.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Rozov, A., Burnashev, N., Sakmann, B. & Neher, E. Transmitter release modulation by intracellular Ca2+ buffers in facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific difference in presynaptic calcium dynamics. J. Physiol. (Lond.) 531, 807–826 (2001).Ca2+ buffers are used to provide evidence for different channel–vesicle spacing at physiologically distinct synaptic connections of the same neuron. Facilitating synapses have wider spacing than depressing synapses.

    CAS  Google Scholar 

  119. Sakaba, T. & Neher, E. Quantitatiave relationship between transmitter release and calcium current at the calyx of Held synapse. J. Neurosci. 21, 462–476 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Delaney, K. R. in Imaging: a Laboratory Manual (eds Yuste, R., Lanni, F. & Konnerth, A.) 26.1–26.10 (Cold Spring Harbor Laboratory Press, New York, 1999).

    Google Scholar 

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

    PubMed  Google Scholar 

  122. Heidelberger, R. Adenosine triphosphate and the late steps in calcium-dependent exocytosis at a ribbon synapse. J. Gen. Physiol. 111, 225–241 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Ravin, R., Parnas, H., Spira, M. E., Volfovsky, N. & Parnas, I. Simultaneous measurement of evoked release and [Ca2+]i in a crayfish release bouton reveals high affinity of release to Ca2+. J. Neurophysiol. 81, 634–642 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  125. Schneggenburger, R. & Neher, E. Intracellular calcium dependence of transmitter release rates at a fast central synapse. Nature 406, 889–983 (2000).References 124 and 125 used flash photolysis of caged Ca2+ at the calyx of Held to estimate the concentration of intracellular Ca2+ needed to evoke release.

    CAS  PubMed  Google Scholar 

  126. Ohnuma, K., Whim, M. D., Fetter, R. D., Kaczmarek, L. K. & Zucker, R. S. Presynaptic target of Ca2+ action on neuropeptide and acetylcholine release in Aplysia californica. J. Physiol. (Lond.) 535, 647–662 (2001).

    CAS  Google Scholar 

  127. Rettig, J. et al. Alteration of Ca2+ dependence of neurotransmitter release by disruption of Ca2+ channel/syntaxin interaction. J. Neurosci. 17, 6647–6656 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Wu, X. S. & Wu, L. G. Protein kinase C increases the apparent affinity of the release machinery to Ca2+ by enhancing the release machinery downstream of the Ca2+ sensor. J. Neurosci. 21, 7928–7936 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Nguyen, P. V. & Atwood, H. L. Altered impulse activity modifies synaptic physiology and mitochondria in crayfish phasic motor neurons. J. Neurophysiol. 72, 2944–2955 (1994).

    CAS  PubMed  Google Scholar 

  130. Sanes, J. R. & Lichtman, J. W. Can molecules explain long-term potentiation? Nature Neurosci. 2, 597–604 (1999).

    CAS  PubMed  Google Scholar 

  131. Augustine, G. J., Burns, M. E., DeBello, W. M., Pettit, D. L. & Schweizer, F. E. Exocytosis: proteins and perturbations. Annu. Rev. Pharmacol. Toxicol. 36, 659–701 (1996).

    CAS  PubMed  Google Scholar 

  132. Craig, A. M. & Boudin, H. Molecular heterogeneity of central synapses: afferent and target regulation. Nature Neurosci. 4, 569–578 (2001).

    CAS  PubMed  Google Scholar 

  133. Staple, J. K., Osen-Sand, A., Benfenati, F., Pich, E. M. & Catsicas, S. Molecular and functional diversity at synapses of individual neurons in vitro. Eur. J. Neurosci. 9, 721–731 (1997).

    CAS  PubMed  Google Scholar 

  134. Yao, W.-D., Rusch, J., Poo, M.-M. & Wu, C.-F. Spontaneous acetylcholine secretion from developing growth cones of Drosophila central neurons in culture: effects of cAMP-pathway mutations. J. Neurosci. 20, 2626–2637 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Augustin, I., Rosenmund, C., Südhof, T. C. & Brose, N. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 400, 457–461 (1999).

    CAS  PubMed  Google Scholar 

  136. Aravamudan, B., Fergestad, T., Davis, W. S., Rodesch, C. K. & Broadie, K. Drosophila Unc-13 is essential for synaptic transmission. Nature Neurosci. 2, 965–971 (1999).

    CAS  PubMed  Google Scholar 

  137. Rosenmund, C. et al. Differential control of vesicle priming and short-term plasticity by Munc13 isoforms. Neuron 33, 411–424 (2002).In cultured mammalian neurons, synaptic properties can be altered by different isoforms of the vesicle-priming protein Munc 13.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  139. Voets, T. et al. Intracellular calcium dependence of large dense-core vesicle exocytosis in the absence of synaptotagmin I. Proc. Natl Acad. Sci. USA 98, 11680–11685 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Wang, C. T. et al. Synaptotagmin modulation of fusion pore kinetics in regulated exocytosis of dense-core vesicles. Science 294, 1111–1115 (2001).

    CAS  PubMed  Google Scholar 

  141. Verona, M., Zanotti, S., Schäfer, T., Racagni, G. & Popoli, M. Changes of synaptotagmin interaction with t-SNARE proteins in vitro after calcium/calmodulin-dependent phosphorylation. J. Neurochem. 74, 209–221 (2000).

    CAS  PubMed  Google Scholar 

  142. Südhof, T. C. Synaptotagmins: why so many? J. Biol. Chem. 277, 7629–7632 (2002).

    PubMed  Google Scholar 

  143. Mackler, J. M. & Reist, N. E. Mutations in the second C2 domain of synaptotagmin disrupt synaptic transmission at Drosophila neuromuscular junctions. J. Comp. Neurol. 436, 4–16 (2001).

    CAS  PubMed  Google Scholar 

  144. Littleton, J. T., Serano, T. L., Rubin, G. M., Ganetzky, B. & Chapman, E. R. Synaptic function modulated by changes in the ratio of synaptotagmin I and IV. Nature 400, 757–780 (1999).Presents an example of modification of synaptic performance by different isoforms of synaptotagmin.

    CAS  PubMed  Google Scholar 

  145. Pongs, O. et al. Frequenin — a novel calcium binding protein that modulates synaptic efficacy in the Drosophila nervous system. Neuron 11, 15–28 (1993).

    CAS  PubMed  Google Scholar 

  146. Wang, C.-Y. et al. Ca2+ binding protein frequenin mediates GDNF-induced potentiation of Ca2+ channels and transmitter release. Neuron 32, 99–112 (2001).Physiological synaptic performance linked to Ca2+ channel activity is modulated by differential expression of the Ca2+-binding protein frequenin.

    PubMed  Google Scholar 

  147. Rivosecchi, R., Pongs, O., Theil, T. & Mallart, A. Implication of frequenin in the facilitation of transmitter release in Drosophila. J. Physiol. (Lond.) 474, 223–232 (1994).

    CAS  Google Scholar 

  148. Tsujimoto, T., Jeromin, A., Saitoh, N., Roder, J. C. & Takahashi, T. Neuronal calcium sensor 1 and activity-dependent facilitation of P/Q-type calcium currents at presynaptic nerve terminals. Science 295, 2276–2279 (2002).

    CAS  PubMed  Google Scholar 

  149. Hendricks, K. B., Wang, B. Q., Schnieders, E. A. & Thorner, J. Yeast homologue of neuronal frequenin is a regulator of phosphatidylinositol-4-OH kinase. Nature Cell Biol. 1, 234–241 (1999).

    CAS  PubMed  Google Scholar 

  150. Chen, C. Y. et al. Human neuronal calcium sensor-1 shows the highest expression level in cerebral cortex. Neurosci. Lett. 319, 67–70 (2002).

    CAS  PubMed  Google Scholar 

  151. Jeromin, A., Shayan, A. J., Msghina, M., Roder, J. & Atwood, H. L. Crustacean frequenins: molecular cloning and differential localization at neuromuscular junctions. J. Neurobiol. 41, 165–175 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  153. Sanyal, S., Sandstrom, D. J., Hoeffer, C. A. & Ramaswami, M. AP-1 functions upstream of CREB to control synaptic plasticity in Drosophila. Nature 416, 870–874 (2002).

    CAS  PubMed  Google Scholar 

  154. Shupliakov, O., Atwood, H. L., Ottersen, O. P., Storm-Mathisen, J. & Brodin, L. Presynaptic glutamate levels in tonic and phasic motor axons correlate with properties of synaptic release. J. Neurosci. 15, 7168–7180 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Kennedy, K. Monte Carlo Model of Calcium in Presynaptic Nerve Terminals. Thesis, Univ. Toronto (1996).

    Google Scholar 

  156. Burrone, J., Neves, G., Gomis, A., Cooke, A. & Lagnado, L. Endogenous calcium buffers regulate fast exocytosis in the synaptic terminal of retinal bipolar cells. Neuron 33, 101–112 (2002).Provides theoretical and experimental tests of the effects of Ca2+ buffers on transmission.

    CAS  PubMed  Google Scholar 

  157. Bradacs, H., Cooper, R. L., Msghina, M. & Atwood, H. L. Differential physiology and morphology of phasic and tonic motor axons in a crayfish limb extensor muscle. J. Exp. Biol. 200, 677–691 (1997).

    CAS  PubMed  Google Scholar 

  158. Reyes, A. et al. Target-cell-specific facilitation and depression in neocortical circuits. Nature Neurosci. 1, 279–285 (1998).

    CAS  PubMed  Google Scholar 

  159. Dittman, J. S., Kreitzer, A. C. & Regehr, W. G. Interplay between facilitation, depression, and residual calcium at three presynaptic terminals. J. Neurosci. 20, 1374–1385 (2000).Descriptions of case I and case II synaptic differentiation are presented in references 157–159 for both crustacean and mammalian CNS synaptic connections.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 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).Provides the best available evidence for a tightly organized active zone structure.

    CAS  PubMed  Google Scholar 

  161. Govind, C. K., Pearce, J., Wojtowicz, J. M. & Atwood, H. L. 'Strong' and 'weak' synaptic differentiation in the crayfish opener muscle: structural correlates. Synapse 16, 45–58 (1994).

    CAS  PubMed  Google Scholar 

  162. Atwood, H. L., Karunanithi, S., Georgiou, J. & Charlton, M. P. Strength of synaptic transmission at neuromuscular junctions of crustaceans and insects in relation to calcium entry. Invert. Neurosci. 3, 81–87 (1997).

    CAS  PubMed  Google Scholar 

  163. Govind, C. K., Atwood, H. L. & Pearce, J. Inhibitory axoaxonal and neuromuscular synapses in the crayfish opener muscle: membrane definition and ultrastructure. J. Comp. Neurol. 351, 476–488 (1995).Non-uniform separation of Ca2+ channels and docked vesicles is illustrated in the freeze-fracture studies of crustacean synapses described in references 161 and 163.

    CAS  PubMed  Google Scholar 

  164. Foletti, D. L. & Scheller, R. H. Developmental regulation and specific brain distribution of phosphorabphilin. J. Neurosci. 21, 5461–5472 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Schlüter, O. M. et al. Rabphilin knock-out mice reveal that rabphilin is not required for Rab3 function in regulating neurotransmitter release. J. Neurosci. 19, 5834–5846 (1999).

    PubMed  PubMed Central  Google Scholar 

  166. von Kriegstein, K., Schnitz, F., Link, E. & Südhof, T. C. Distribution of synaptic vesicle proteins in the mammalian retina identifies obligatory and facultative components of ribbon synapses. Eur. J. Neurosci. 11, 1335–1348 (1999).

    CAS  PubMed  Google Scholar 

  167. Marquèze, B. et al. Cellular localization of synaptotagmin I, II, and III mRNAs in the central nervous system and pituitary and adrenal glands of the rat. J. Neurosci. 15, 4906–4917 (1995).

    PubMed  PubMed Central  Google Scholar 

  168. Ullrich, B. et al. Functional properties of multiple synaptotagmins in brain. Neuron 13, 1281–1291 (1994).

    CAS  PubMed  Google Scholar 

  169. Li, J.-Y., Jahn, R. & Dahlström, A. Synaptotagmin I is present mainly in autonomic and sensory neurons of the rat peripheral nervous system. Neuroscience 63, 837–850 (1994).

    CAS  PubMed  Google Scholar 

  170. Südhof, T. C. et al. Synapsins: mosaics of shared and individual domains in a family of synaptic vesicle phosphoproteins. Science 245, 1474–1480 (1989).

    PubMed  Google Scholar 

  171. Mandell, J. W. et al. Synapsins in the vertebrate retina: absence from ribbon synapses and heterogeneous distribution among conventional synapses. Neuron 5, 19–33 (1990).

    CAS  PubMed  Google Scholar 

  172. Li, L. et al. Impairment of synaptic vesicle clustering and of synaptic transmission, and increased seizure propensity, in synapsin I-deficient mice. Proc. Natl Acad. Sci. USA 92, 9235–9239 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Volknandt, W., Hausinger, A., Wittich, B. & Zimmermann, H. The synaptic vesicle-associated G protein o-rab3 is expressed in subpopulations of neurons. J. Neurochem. 60, 851–857 (1993).

    CAS  PubMed  Google Scholar 

  174. Geppert, M., Goda, Y., Stevens, C. F. & Südhof, T. C. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature 387, 810–814 (1997).

    CAS  PubMed  Google Scholar 

  175. Castillo, P. E. et al. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature 388, 590–592 (1997).

    CAS  PubMed  Google Scholar 

  176. Marquèze-Pouey, B., Wisden, W., Malosio, M. L. & Betz, H. Differential expression of synaptophysin and synaptoporin mRNAs in the postnatal rat central nervous system. J. Neurosci. 11, 3388–3397 (1991).

    PubMed  PubMed Central  Google Scholar 

  177. Fykse, E. M. et al. Relative properties and localizations of synaptic vesicle protein isoforms: the case of the synaptophysins. J. Neurosci. 13, 4997–5007 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Janz, R. et al. Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron 24, 687–700 (1999).

    CAS  PubMed  Google Scholar 

  179. McMahon, H. T. et al. Synaptophysin, a major synaptic vesicle protein, is not essential for neurotransmitter release. Proc. Natl Acad. Sci. USA 93, 4760–4764 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Bajjalieh, S. M., Frantz, G. D., Weimann, J. M., McConnell, S. K. & Scheller, R. H. Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J. Neurosci. 14, 5223–5235 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Janz, R. & Südhof, T. C. SV2C is a synaptic vesicle protein with an unusually restricted localization: anatomy of a synaptic vesicle protein family. Neuroscience 94, 1279–1290 (1999).

    CAS  PubMed  Google Scholar 

  182. Xu, T. & Bajjalieh, S. M. SV2 modulates the size of the readily releasable pool of secretory vesicles. Nature Cell Biol. 3, 691–698 (2001).

    CAS  PubMed  Google Scholar 

  183. Janz, R., Goda, Y., Geppert, M., Missler, M. & Südhof, T. C. SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron 24, 1003–1016 (1999).

    CAS  PubMed  Google Scholar 

  184. Trimble, W. S., Gray, T. S., Elferink, L. S., Wilson, M. C. & Scheller, R. H. Distinct patterns of expression of two VAMP genes within the rat brain. J. Neurosci. 10, 1380–1387 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Deitcher, D. L. et al. Distinct requirements for evoked and spontaneous release of neurotransmitter are revealed by mutations in the Drosophila gene neuronal-synaptobrevin. J. Neurosci. 18, 2028–2039 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Janz, R., Hofmann, K. & Südhof, T. C. SVOP, an evolutionarily conserved synaptic vesicle protein, suggests novel transport functions of synaptic vesicles. J. Neurosci. 18, 9269–9281 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Kohan, S. A. et al. Cysteine string protein immunoreactivity in the nervous system and adrenal gland of rat. J. Neurosci. 15, 6230–6238 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Dawson-Scully, K., Bronk, P., Atwood, H. L. & Zinsmaier, K. E. Cysteine-string protein increases the calcium sensitivity of late steps in fast neurotransmitter exocytosis. J. Neurosci. 20, 6039–6047 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Chen, S. et al. Enhancement of presynaptic calcium current by cysteine string protein. J. Physiol. (Lond.) 538, 383–389 (2002).

    CAS  Google Scholar 

  191. Ruiz-Montasell, B. et al. Differential distribution of syntaxin isoforms 1A and 1B in the rat central nervous system. Eur. J. Neurosci. 8, 2544–2552 (1996).

    CAS  PubMed  Google Scholar 

  192. Fergestad, T. et al. Targeted mutations in the syntaxin H3 domain specifically disrupt SNARE complex function in synaptic transmission. J. Neurosci. 21, 9142–9150 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Boschert, U. et al. Developmental and plasticity-related differential expression of two SNAP-25 isoforms in the rat brain. J. Comp. Neurol. 367, 177–193 (1996).

    CAS  PubMed  Google Scholar 

  194. Raber, J. et al. Coloboma hyperactive mutant mice exhibit regional and transmitter-specific deficits in neurotransmission. J. Neurochem. 68, 176–186 (1997).

    CAS  PubMed  Google Scholar 

  195. Rohrbough, J., Grotewiel, M. S., Davis, R. L. & Broadie, K. Integrin-mediated regulation of synaptic morphology, transmission, and plasticity. J. Neurosci. 20, 6868–6878 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Lahey, T., Gorczyca, M., Jia, X.-X. & Budnik, V. The Drosophila tumor suppressor gene dlg is required for normal synaptic bouton structure. Neuron 13, 823–835 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Budnik, V. et al. Regulation of synapse structure and function by the Drosophila tumor suppressor gene dlg. Neuron 17, 627–640 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Olafsson, P., Wang, T. & Lu, B. Molecular cloning and functional characterization of the Xenopus Ca2+-binding protein frequenin. Proc. Natl Acad. Sci. USA 92, 8001–8005 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Fenster, S. D. et al. Piccolo, a presynaptic zinc finger protein structurally related to Bassoon. Neuron 25, 203–214 (2000).

    CAS  PubMed  Google Scholar 

  200. Brandstatter, J. H., Fletcher, E. L., Garner, C. C., Gunderfinger, E. D. & Wassle, H. Differential expression of the presynaptic cytomatrix protein bassoon among ribbon synapses in the mammalian retina. Eur. J. Neurosci. 11, 3683–3693 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Hegström-Wojtowicz for help in preparing the manuscript. L. Marin provided help with electron microscopy (presented in figure 4b); A. Miller, H. Bradacs and M. P. Charlton contributed to recent work on crustacean neuromuscular junctions. The authors' research is supported by the Natural Sciences and Engineering Research Council of Canada, and by the Canadian Institutes of Health Research. The authors dedicate this review to the memory of Professor C. K. Govind, University of Toronto, a significant contributor to crustacean synaptic biology, who died on 24 May 2002.

Author information

Authors and Affiliations

  1. Department of Physiology, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Harold L. Atwood & Shanker Karunanithi

Authors
  1. Harold L. Atwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shanker Karunanithi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harold L. Atwood.

Related links

Related links

DATABASES

LocusLink

frequenin

KV1 channels

Munc 13

N-type Ca2+ channels

P/Q-type Ca2+ channels

R-type Ca2+ channels

SNAP-25

synaptobrevin

synaptotagmin

syntaxin

T-type Ca2+ channels

FURTHER INFORMATION

Encyclopedia of Life Sciences

calcium and neurotransmitter release

chemical synapses

long-term depression and depotentiation

long-term potentiation

synapses

synaptic plasticity: short term

synaptic vesicle traffic

Glossary

SYNAPTIC STRENGTH

The relative amplitude of the postsynaptic response that is generated by the activity of the presynaptic neuron.

ACTIVE ZONE

The site of the presynaptic terminal at which synaptic exocytosis occurs.

CLIMBING FIBRES

Cerebellar afferents that arise from the inferior olivary nucleus, each of which forms multiple synapses with a single Purkinje cell.

PARALLEL FIBRES

Axons of cerebellar granule cells. Parallel fibres emerge from the molecular layer of the cerebellar cortex towards the periphery, where they extend branches perpendicular to the main axis of the Purkinje neurons and form the so-called en passant synapses with this cell type.

QUANTAL SIZE

The mean amplitude of the postsynaptic response that results from the release of transmitter from a single synaptic vesicle.

HIPPOCAMPAL MOSSY FIBRES

Axons of granule cells, which form synapses with CA3 pyramidal neurons. Mossy fibre boutons are among the largest in the central nervous system.

READILY RELEASABLE VESICLES

Synaptic vesicles that are available for rapid fusion with the presynaptic membrane on arrival of a nerve impulse. They are docked to the membrane and have been biochemically primed for release.

VESICLE PRIMING

Primed vesicles are those that have acquired the biochemical attributes for fusion with the presynaptic membrane; they can release their transmitter on the arrival of a nerve impulse.

LONG-TERM POTENTIATION

A long-lasting increase in the efficacy of neurotransmission, which can be elicited by diverse patterns of synaptic activation.

QUANTAL VARIANCE

A measure of the variability of quantal events normalized to their mean amplitude. From the statistical point of view, quantal variance corresponds to the coefficient of variation of the responses — the standard deviation divided by the mean.

AMPEROMETRY

An electroanalytical technique that is based on the measurement of current flow through an electrochemical cell. In the case of exocytosis, the release of oxidizable substances (such as catecholamines) from single vesicles can be studied by amperometry using a carbon fibre electrode. The electrode is held at a voltage that causes the oxidation of the transmitter, and the resulting redox currents are measured with a patch-clamp amplifier.

DOCKED VESICLES

Synaptic vesicles that are tethered to the presynaptic membrane or the active zone structure. According to current views, not all docked vesicles are fully primed for fusion and release of transmitter.

SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells that form synapses with the apical dendrites of hippocampal CA1 neurons.

FREEZE FRACTURE

An electron-microscopic method in which rapidly frozen tissue is cracked to produce a fracture plane through the specimen. The surface of the fracture plane is shadowed by a heavy metal, and the specimen is digested away to leave a replica that can be examined under the electron microscope.

ATOMIC FORCE MICROSCOPY

A form of microscopy in which a probe is mechanically tracked over a surface of interest in a series of x–y scans. The force found at each coordinate is measured with piezoelectric sensors, providing information about the chemical nature of a surface.

ELECTRON MICROSCOPE TOMOGRAPHY

A method for the three-dimensional reconstruction of objects from a series of projection images that are recorded with a transmission electron microscope. It offers the opportunity to obtain spatial information on structural arrangements of cellular components.

PRESYNAPTIC GRID

A dense matrix of proteins that is associated with the active zone, which is thought to have a crucial role in defining the transmitter release sites.

MELANOTROPHS

Excitable cells from the pituitary that are specialized in secreting several peptide hormones such as β-endorphin and adrenocorticotropin.

SNARE PROTEINS

A family of membrane-tethered coiled-coil proteins that regulate exocytic reactions and target specificity in vesicular fusion processes. SNARE stands for 'soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor'.

CHROMAFFIN CELLS

Cells of the adrenal gland that store and secrete catecholamines. They are known as 'chromaffin' cells because of the ability of chromium salts to stain them.

CAGED MOLECULE

A labile derivative of a biologically active molecule that will break down after photolysis of the precursor to yield the bioactive compound.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Atwood, H., Karunanithi, S. Diversification of synaptic strength: presynaptic elements. Nat Rev Neurosci 3, 497–516 (2002). https://doi.org/10.1038/nrn876

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn876

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing