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.

Coordinated multivesicular release at a mammalian ribbon synapse

Abstract

Traditional models of synaptic transmission hold that release sites within an active zone operate independently. Although the release of multiple vesicles (multivesicular release; MVR) from single active zones occurs at some central synapses, MVR is not thought to require coordination among release sites. Ribbon synapses seem to be optimized to release many vesicles over an extended period, but the dynamics of MVR at ribbon synapses is unknown. We examined MVR at a ribbon synapse in a retinal slice preparation using paired recordings from presynaptic rod bipolar and postsynaptic AII amacrine cells. When evoked release was highly desynchronized, discrete postsynaptic events were larger than quantal miniature excitatory postsynaptic currents (mEPSCs) but had the same time course. The amplitude of these multiquantal mEPSCs, which seem to arise from the essentially simultaneous release of multiple vesicles, was reduced by lowering release probability. The release synchrony reflected in these multivesicular events suggests that release within an active zone is coordinated during MVR.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: PPD of tEPSCs is presynaptic and reduces MVR.
Figure 2: Quantal content of tEPSC exceeds the number of connections between an RBC-AII cell pair.
Figure 3: Spontaneous mEPSCs are uniquantal.
Figure 4: Analysis of asynchronous release reveals MVR.
Figure 5: MVR is observed when release is desynchronized.
Figure 6: MVR obeys binomial statistics.

References

  1. Propst, J.W. & Ko, C.P. Correlations between active zone ultrastructure and synaptic function studied with freeze-fracture of physiologically identified neuromuscular junctions. J. Neurosci. 7, 3654–3664 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Katz, B. The Release of Neural Transmitter Substances (Liverpool University Press, Liverpool, UK, 1969).

    Google Scholar 

  3. Redman, S. Quantal analysis of synaptic potentials in neurons of the central nervous system. Physiol. Rev. 70, 165–198 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Korn, H. & Faber, D.S. Quantal analysis and synaptic efficacy in the CNS. Trends Neurosci. 14, 439–445 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Silver, R.A., Momiyama, A. & Cull-Candy, S.G. Locus of frequency-dependent depression identified with multiple-probability fluctuation analysis at rat climbing fibre-Purkinje cell synapses. J. Physiol. 510, 881–902 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tong, G. & Jahr, C.E. Multivesicular release from excitatory synapses of cultured hippocampal neurons. Neuron 12, 51–59 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Auger, C., Kondo, S. & Marty, A. Multivesicular release at single functional synaptic sites in cerebellar stellate and basket cells. J. Neurosci. 18, 4532–4547 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Oertner, T.G., Sabatini, B.L., Nimchinsky, E.A. & Svoboda, K. Facilitation at single synapses probed with optical quantal analysis. Nat. Neurosci. 5, 657–664 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. von Gersdorff, H., Vardi, E., Matthews, G. & Sterling, P. Evidence that vesicles on the synaptic ribbon of retinal bipolar neurons can be rapidly released. Neuron 16, 1221–1227 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Heidelberger, R., Heinemann, C., Neher, E. & Matthews, G. Calcium dependence of the rate of exocytosis in a synaptic terminal. Nature 371, 513–515 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. von Gersdorff, H. & Matthews, G. Depletion and replenishment of vesicle pools at a ribbon-type synaptic terminal. J. Neurosci. 17, 1919–1927 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Parsons, T.D. & Sterling, P. Synaptic ribbon: conveyor belt or safety belt. Neuron 37, 379–382 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Strettoi, E., Dacheux, R.F. & Raviola, E. Synaptic connections of rod bipolar cells in the inner plexiform layer of the rabbit retina. J. Comp. Neurol. 295, 449–466 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Chun, M.H., Han, S.H., Chung, J.W. & Wassle, H. Electron microscopic analysis of the rod pathway of the rat retina. J. Comp. Neurol. 332, 421–432 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Tong, G. & Jahr, C.E. Block of glutamate transporters potentiates postsynaptic excitation. Neuron 13, 1195–1203 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Singer, J.H. & Diamond, J.S. Sustained Ca2+ entry elicits transient postsynaptic currents at a retinal ribbon synapse. J. Neurosci. 23, 10923–10933 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cui, J., Ma, Y.P., Lipton, S.A. & Pan, Z.H. Glycine receptors and glycinergic synaptic input at the axon terminals of mammalian retinal rod bipolar cells. J. Physiol. 553, 895–909 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hartveit, E. Reciprocal synaptic interactions between rod bipolar cells and amacrine cells in the rat retina. J. Neurophysiol. 81, 2923–2936 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Koulen, P. et al. Presynaptic and postsynaptic localization of GABAB receptors in neurons of the rat retina. Eur. J. Neurosci. 10, 1446–1456 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. Muresan, V., Lyass, A. & Schnapp, B.J. The kinesin motor KIF3A is a component of the presynaptic ribbon in vertebrate photoreceptors. J. Neurosci. 19, 1027–1037 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Young, H.M. & Vaney, D.I. Rod-signal interneurons in the rabbit retina: 1. rod bipolar cells. J. Comp. Neurol. 310, 139–153 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Li, W., Trexler, E.B. & Massey, S.C. Glutamate receptors at rod bipolar ribbon synapses in the rabbit retina. J. Comp. Neurol. 448, 230–248 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Strettoi, E., Raviola, E. & Dacheux, R.F. Synaptic connections of the narrow-field, bistratified rod amacrine cell (AII) in the rabbit retina. J. Comp. Neurol. 325, 152–168 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Vaney, D.I., Gynther, I.C. & Young, H.M. Rod-signal interneurons in the rabbit retina: 2. AII amacrine cells. J. Comp. Neurol. 310, 154–169 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Sterling, P., Freed, M.A. & Smith, R.G. Architecture of rod and cone circuits to the on-beta ganglion cell. J. Neurosci. 8, 623–642 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. del Castillo, J. & Katz, B. Quantal components of the end-plate potential. J. Physiol. 124, 157–181 (1954).

    Article  Google Scholar 

  31. Van der Kloot, W. Estimating the timing of quantal releases during end-plate currents at the frog neuromuscular junction. J. Physiol. 402, 595–603 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. 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 

  34. Lagnado, L., Gomis, A. & Job, C. Continuous vesicle cycling in the synaptic terminal of retinal bipolar cells. Neuron 17, 957–967 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Slaughter, M.M. & Miller, R.F. 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science 211, 182–185 (1981).

    Article  CAS  PubMed  Google Scholar 

  37. Otsu, Y. et al. Competition between phasic and asynchronous release for recovered synaptic vesicles at developing hippocampal autaptic synapses. J. Neurosci. 24, 420–433 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Euler, T. & Masland, R.H. Light-evoked responses of bipolar cells in a mammalian retina. J. Neurophysiol. 83, 1817–1829 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Matsui, K. & Jahr, C.E. Ectopic release of synaptic vesicles. Neuron 40, 1173–1183 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Alvarez deToledo, G. & Fernandez, J.M. Compound versus multigranular exocytosis in peritoneal mast cells. J. Gen. Physiol. 95, 397–409 (1990).

    Article  CAS  Google Scholar 

  42. Hansen, N.J., Antonin, W. & Edwardson, J.M. Identification of SNAREs involved in regulated exocytosis in the pancreatic acinar cell. J. Biol. Chem. 274, 22871–22876 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Alvarez deToledo, G., Fernandez-Chacon, R. & Fernandez, J.M. Release of secretory products during transient vesicle fusion. Nature 363, 554–558 (1993).

    Article  CAS  Google Scholar 

  44. Barlow, H.B., Levick, W.R. & Yoon, M. Responses to single quanta of light in retinal ganglion cells of the cat. Vision Res. 3 (Suppl.), 87–101 (1971).

    Article  PubMed  Google Scholar 

  45. Sakitt, B. Counting every quantum. J. Physiol. 223, 131–150 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nelson, R. AII amacrine cells quicken time course of rod signals in the cat retina. J. Neurophysiol. 47, 928–947 (1982).

    Article  CAS  PubMed  Google Scholar 

  47. Field, G.D. & Rieke, F. Nonlinear signal transfer from mouse rods to bipolar cells and implications for visual sensitivity. Neuron 34, 773–785 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Faber, S. Massey, P. Sterling and L.-G. Wu for helpful discussions. This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program, a National Institute of Neurological Disorders and Stroke Career Development Award to J.H.S., EY11105 (to N.V.) and EY00828 (to P. Sterling, supporting L.L.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joshua H Singer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singer, J., Lassová, L., Vardi, N. et al. Coordinated multivesicular release at a mammalian ribbon synapse. Nat Neurosci 7, 826–833 (2004). https://doi.org/10.1038/nn1280

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1280

This article is cited by

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