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.

  • Letter
  • Published:

Rab3A is essential for mossy fibre long-term potentiation in the hippocampus

Nature volume 388, pages 590–593 (1997)Cite this article

Abstract

Repetitive activation of excitatory synapses in the central nervous system results in a long-lasting increase in synaptic transmission called long-term potentiation (LTP). It is generally believed that this synaptic plasticity may underlie certain forms of learning and memory. LTP at most synapses involves the activation of the NMDA (N-methyl-d-aspartate) subtype of glutamate receptor, but LTP at hippocampal mossy fibre synapses is independent of NMDA receptors and has a component that is induced and expressed presynaptically1. It appears to be triggered by a rise in presynaptic Ca2+(refs 2, 3), and requires the activation of protein kinase A4,5,6, which leads to an increased release of glutamate3,7,8,9,10. Agreat deal is known about the biochemical steps involved in the vesicular release of transmitter11,12,13, but none of these steps has been directly implicated in long-term synaptic plasticity. Here we show that, although a variety of short-term plasticities are normal, LTP at mossy fibre synapses is abolished in mice lacking the synaptic vesicle protein Rab3A.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Immunohistochemical analysis of the Rab3 proteins in hippocampus.
Figure 2: Mossy fibre synaptic inputs are normal in Rab3eficient mice.
Figure 3: Synaptic transmission in Rab3eficient mice.
Figure 4: Mossy fibre LTP is blocked in Rab3eficient mice.

Similar content being viewed by others

References

  1. Nicoll, R. A. & Malenka, R. C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377, 115–118 (1995).

    Article  ADS  CAS  Google Scholar 

  2. Castillo, P. E., Weisskopf, M. G. & Nicoll, R. A. The role of Ca2+ channels in hippocampal mossy fiber synaptic transmission and long-term potentiation. Neuron 12, 261–269 (1994).

    Article  CAS  Google Scholar 

  3. Tong, G., Malenka, R. C. & Nicoll, R. A. Long-term potentiation in cultures of single hippocampal granule cells: A presynaptic form of plasticity. Neuron 16, 1147–1157 (1996).

    Article  CAS  Google Scholar 

  4. Weisskopf, M. G., Castillo, P. E., Zalutsky, R. A. & Nicoll, R. A. Mediation of hippocampal mossy fiber long-term potentiation by cyclic AMP. Science 265, 1878–1882 (1994).

    Article  ADS  CAS  Google Scholar 

  5. Huang, Y-Y., Li, X.-C. & Kandel, E. cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase. Cell 79, 69–79 (1994).

    Article  CAS  Google Scholar 

  6. Huang, Y. Y.et al. Agenetic test of the effects of mutations in PKA on mossy fiber LTP and its relation to spatial and contextual learning. Cell 83, 1211–1222 (1995).

    Article  CAS  Google Scholar 

  7. Zalutsky, R. A. & Nicoll, R. A. Comparison of two forms of long-term potentiation in single hippocampal neurons. Science 248, 1619–1624 (1990).

    Article  ADS  CAS  Google Scholar 

  8. Weisskopf, M. G. & Nicoll, R. A. Presynaptic changes during mossy fiber LTP revealed by NMDA receptor-mediated synaptic responses. Nature 376, 256–259 (1995.).

    Article  ADS  CAS  Google Scholar 

  9. López-García, J. C., Arancio, O., Kandel, E. R. & Baranes, D. Apresynaptic locus for long-term potentiation of elementary synaptic transmission at mossy fiber synapses in culture. Proc. Natl Acad. Sci. USA 93, 4712–4717 (1996).

    Article  ADS  Google Scholar 

  10. Xiang, Z., Greenwood, A. C., Kairiss, E. W. & Brown, T. H. Quantal mechanism of long-term potentiation in hippocampal mossy-fiber synapses. J. Neurophysiol. 71, 2552–2556 (1994).

    Article  CAS  Google Scholar 

  11. Ferro-Novick, S. & Jahn, R. Vesicle fusion from yeast to man. Nature 370, 191–193 (1994).

    Article  ADS  CAS  Google Scholar 

  12. Bennett, M. K. & Scheller, R. H. Amolecular description of synaptic vesicle membrane trafficking. Annu. Rev. Biochem. 63, 63–100 (1994).

    Article  CAS  Google Scholar 

  13. Südhof, T. C. The synaptic vesicle cycle: a cascade of protein–protein interactions. Nature 375, 645–653 (1995).

    Article  ADS  Google Scholar 

  14. DeCamilli, P., Benfenati, F., Valtorta, F. & Greengard, P. The synapsins. Annu. Rev. Cell Biol. 6, 433–460 (1990).

    Article  CAS  Google Scholar 

  15. Spillane, D. M., Rosahl, T. W., Südhof, T. C. & Malenka, R. C. Long-term potentiation in mice lacking synapsins. Neuropharmacology 34, 1573–1579 (1995).

    Article  CAS  Google Scholar 

  16. Fykse, E. M., Li, C. & Südhof, T. C. Phosphorylation of rabphilin-3A by Ca2+/calmodulin- and cAMP-dependent protein kinases in vitro. J. Neurosci. 15, 2385–2395 (1995).

    Article  CAS  Google Scholar 

  17. Wang, Y., Okamoto, M., Schmitz, F., Hofmann, K. & Südhof, T. C. Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature 387, 000–000 (1997).

    Article  Google Scholar 

  18. Geppert, M.et al. The role of Rab3A in neurotransmitter release. Nature 369, 493–497 (1994).

    Article  ADS  CAS  Google Scholar 

  19. Rosahl, T. W.et al. Essential functions of synapsins I and II in synaptic vesicle regulation. Nature 375, 488–493 (1995).

    Article  ADS  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. Kamiya, H., Shinozaki, H. & Yamamoto, C. Activation of metabotropic glutamate receptor type 2/3 suppresses transmission at rat hippocampal mossy fibre synapses. J. Physiol. (Lond.) 493, 447–455 (1996).

    Article  CAS  Google Scholar 

  22. Yokoi, M.et al. Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2. Science 273, 645–647 (1996).

    Article  ADS  CAS  Google Scholar 

  23. Zucker, R. S. Short-term synaptic plasticity. Annu. Rev. Neurosci. 12, 13–31 (1989).

    Article  CAS  Google Scholar 

  24. Geppert, M., Goda, Y., Stevens, C. F. & Südhof, T. C. Rab3A regulates a late step in synaptic vesicle fusion. Nature 387, 810–814 (1997).

    Article  ADS  CAS  Google Scholar 

  25. Regehr, W. G., Delaney, K. R. & Tank, D. W. The role of presynaptic calcium in short-term enhancement at the hippocampal mossy fiber synapse. J. Neurosci. 14, 523–537 (1994).

    Article  CAS  Google Scholar 

  26. Salin, P. A., Scanziani, M., Malenka, R. C. & Nicoll, R. A. Distinct short-term plasticity at two excitatory synapses in the hippocampus. Proc. Natl Acad. Sci. USA 93, 13304–13309 (1996).

    Article  ADS  CAS  Google Scholar 

  27. Seamon, K. B. & Daly, J. W. Forskolin: Its biological and chemical properties. Adv. Cyclic Nucleot. Prot. Phosphoryl. Res. 20, 1–150 (1986).

    CAS  Google Scholar 

  28. Dixon, D. & Atwood, L. Adenylate cyclase system is essential for long-term facilitation at the crayfish neuromuscular junction. J. Neurosci. 9, 4246–4252 (1989).

    Article  CAS  Google Scholar 

  29. Schacher, S., Castellucci, V. F. & Kandel, E. R. cAMP evokes long-term facilitation in Aplysia sensory neurons that requires new protein synthesis. Science 240, 1667–1669 (1988).

    Article  ADS  CAS  Google Scholar 

  30. Li, C.et al. Synaptic targeting of rabphilin-3A, a synaptic vesicle Ca2+/phospholipid-binding protein, depends on rab3A/3C. Neuron 13, 885–898 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Czerwonka for secretarial assistance. R.A.N. is a member of the Keck Center for Integrative Neuroscience and the Silvio Conte Center for Neuroscience Research. R.C.M. is a member of the Center for Neurobiology and Psychiatry, and the Center for the Neurobiology of Addiction. R.A.N. and R.C.M. are supported by grants from the NIH. T.C.S. was supported by grants from the HFJP and the W.M. Keck Foundation. R.J. was supported by a postdoctoral fellowship from DFG.

Author information

Author notes

  1. Pablo E. Castillo

    Present address: Departamento de Fisiologia, Facultad de Medicina, Gral Flores 2125, Montevideo, Uruguay

Authors and Affiliations

  1. Departments of Cellular and Molecular Pharmacology, San Francisco, 94143, California, USA

    Pablo E. Castillo & Roger A. Nicoll

  2. Departments of Psychiatry and San Francisco, 94143, California, USA

    Thanos Tzounopoulos & Robert C. Malenka

  3. Departments of Physiology, University of California, San Francisco, 94143, California, USA

    Robert C. Malenka & Roger A. Nicoll

  4. Department of Molecular Genetics and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, 75235, Texas, USA

    Roger Janz & Thomas C. Sdhof

Authors
  1. Pablo E. Castillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roger Janz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas C. Sdhof
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thanos Tzounopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert C. Malenka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roger A. Nicoll
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roger A. Nicoll.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castillo, P., Janz, R., Sdhof, T. et al. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature 388, 590–593 (1997). https://doi.org/10.1038/41574

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/41574

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