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.

  • Article
  • Published:

PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation

Nature Neuroscience volume 4, pages 19–28 (2001)Cite this article

Abstract

Signaling mechanisms underlying neurotrophic regulation of synaptic transmission are not fully understood. Here we show that neurotrophin-3 (NT3)-induced potentiation of synaptic transmission at the neuromuscular synapses is blocked by inhibition of phosphoinositide-3 kinase, phospholipase C-γ or the downstream IP3 receptors of phospholipase C-γ, but not by inhibition of MAP kinase. However, neither stimulation of Ca2+ release from intracellular stores by photolysis of caged IP3, nor expression of a constitutively active phosphoinositide-3 kinase (PI3K*) in presynaptic motoneurons alone is sufficient to enhance transmission. Photo-uncaging of IP3 in neurons expressing PI3K* elicits a marked synaptic potentiation, mimicking the NT3 effect. These results reveal an involvement of PI3 kinase in transmitter release, and suggest that concomitant activation of PI3 kinase and IP3 receptors is both necessary and sufficient to mediate the NT3-induced synaptic potentiation.

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: Immunocytochemical detection of activation of MAP kinase and PI3 kinase pathways.
Figure 2: NT3-induced Ca2+ release from intracellular stores depends on PLC-γ and IP3.
Figure 3: NT3-induced potentiation of SSCs at NMJ requires activation of PI3 kinase and PLC-γ, but not MAP kinase.
Figure 4: Dominant negative PI3 kinase prevents the effect of NT3.
Figure 5: Continuous activation of PI3 kinase is required for NT3-induced synaptic potentiation.
Figure 6: Concomitant activation of PI3 kinase and IP3 receptors enhances transmitter release.
Figure 7: NT3-induced enhancement of evoked synaptic transmission is blocked by inhibition of PI3 kinase or IP3 receptors.
Figure 8: NT3 potentiates spontaneous transmitter release at the NMJ in Xenopus tadpoles in vivo.

Similar content being viewed by others

References

  1. Lewin, G. R. & Barde, Y.-A. Physiology of the neurotrophins. Annu. Rev. Neurosci. 19, 289–317 (1996).

    Article  CAS  Google Scholar 

  2. Lu, B. & Chow, A. Neurotrophins and hippocampal synaptic plasticity. J. Neurosci. Res. 58, 76–87 (1999).

    Article  CAS  Google Scholar 

  3. McAllister, A. M., Katz, L. C. & Lo, D. C. Neurotrophins and synaptic plasticity. Annu. Rev. Neurosci. 22, 295–318 (1999).

    Article  CAS  Google Scholar 

  4. Kim, H. G., Wang, T., Olafsson, P. & Lu, B. Neurotrophin-3 potentiates neuronal activity and inhibits γ-aminobutyrateric synaptic transmission in cortical neurons. Proc. Natl. Acad. Sci. USA 91, 12341–12345 (1994).

    Article  CAS  Google Scholar 

  5. Lessmann, V., Gottmann, K. & Heumann, R. BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurons. Neuroreport 6, 21–25 (1994).

    Article  CAS  Google Scholar 

  6. Levine, E. S., Dreyfus, C. F., Black, I. B. & Plummer, M. R. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc. Natl. Acad. Sci. USA 92, 8074–8077 (1995).

    Article  CAS  Google Scholar 

  7. Takei, N. et al. Brain-derived neurotrophic factor increases the stimulation-evoked release of glutamate and the levels of exocytosis-associated proteins in cultured cortical neurons from embryonic rats. J. Neurochem. 68, 370–375 (1997).

    Article  CAS  Google Scholar 

  8. Korte, M. et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA 92, 8856–8860 (1995).

    Article  CAS  Google Scholar 

  9. Figurov, A., Pozzo-Miller, L., Olafsson, P., Wang, T. & Lu, B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709 (1996).

    Article  CAS  Google Scholar 

  10. Patterson, S. L. et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16, 1137–1145 (1996).

    Article  CAS  Google Scholar 

  11. Gottschalk, W., Pozzo-Miller, L. D., Figurov, A. & Lu, B. Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J. Neurosci. 18, 6830–6839 (1998).

    Article  CAS  Google Scholar 

  12. Pozzo-Miller, L. et al. Impairments in high frequency transmission, synaptic vesicle docking and synaptic protein distribution in the hippocampus of BDNF knockout mice. J. Neurosci. 19, 4972–4983 (1999).

    Article  CAS  Google Scholar 

  13. Xu, B. et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J. Neurosci. 20, 6888–6897 (2000).

    Article  CAS  Google Scholar 

  14. Lohof, A. M., Ip, N. Y. & Poo, M.-m. Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature 363, 350–353 (1993).

    Article  CAS  Google Scholar 

  15. Stoop, R. & Poo, M.-m. Potentiation of transmitter release by ciliary neurotrophic factor requires somatic signaling. Science 267, 695–699 (1995).

    Article  CAS  Google Scholar 

  16. Chang, S. & Popov, S. V. Long-range signaling within growing neurites mediated by neurotrophin-3. Proc. Natl. Acad. Sci. USA 96, 4095–4100 (1999).

    Article  CAS  Google Scholar 

  17. Wang, X. H. & Poo, M.-m. Potentiation of developing synapses by postsynaptic release of neurotrophin-4. Neuron 19, 825–835 (1997).

    Article  CAS  Google Scholar 

  18. Xie, K., Wang, T., Olafsson, P., Mizuno, K. & Lu, B. Activity-dependent expression of NT-3 in muscle cells in culture: implication in the development of neuromuscular junctions. J. Neurosci. 17, 2947–2958 (1997).

    Article  CAS  Google Scholar 

  19. Barbacid, M. Nerve growth factor: a tale of two receptors. Oncogene 8, 2033–2042 (1993).

    CAS  PubMed  Google Scholar 

  20. Kaplan, D. R. & Stephens, R. M. Neurotrophin signal transduction by the Trk receptor. J. Neurobiol. 25, 1404–1417 (1994).

    Article  CAS  Google Scholar 

  21. Segal, R. A. & Greenberg, M. E. Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 19, 463–489 (1996).

    Article  CAS  Google Scholar 

  22. Kaplan, D. R. & Miller, F. D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391 (2000).

    Article  CAS  Google Scholar 

  23. Toker, A. & Cantley, L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387, 673–676 (1997).

    Article  CAS  Google Scholar 

  24. Atwal, J. K., Massie, B., Miller, F. D. & Kaplan, D. R. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 27, 265–277 (2000).

    Article  CAS  Google Scholar 

  25. Song, H. et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281, 1515–1518 (1998).

    Article  CAS  Google Scholar 

  26. Gottschalk, W. A. et al. Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. Learn. Mem. 6, 243–256 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Stoop, R. & Poo, M.-m. Synaptic modulation by neurotrophic factors: differential and synergistic effects of brain-derived neurotrophic factor and ciliary neurotrophic factor. J. Neurosci. 16, 3256–3264 (1996).

    Article  CAS  Google Scholar 

  28. He, X., Yang, F., Xie, Z. & Lu, B. Intracellular Ca2+ and Ca2+/calmodulin-dependent kinase II mediate acute potentiation of neurotransmitter release by neurotrophin-3. J. Cell Biol. 149, 783–792 (2000).

    Article  CAS  Google Scholar 

  29. Gunn-Moore, F. J., Williams, A. G. & Tavare, J. M. Analysis of mitogen-activated protein kinase activation by naturally occurring splice variants of TrkC, the receptor for neurotrophin-3. Biochem. J. 322, 193–198 (1997).

    Article  CAS  Google Scholar 

  30. Holm, N. R., Christophersen, P., Olesen, S. P. & Gammeltoft, S. Activation of calcium-dependent potassium channels in rat brain neurons by neurotrophin-3 and nerve growth factor. Proc. Natl. Acad. Sci. USA 94, 1002–1006 (1997).

    Article  CAS  Google Scholar 

  31. Skaper, S. D., Floreani, M., Negro, A., Facci, L. & Giusti, P. Neurotrophins rescue cerebellar granule neurons from oxidative stress-mediated apoptotic death: selective involvement of phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathway. J. Neurochem. 70, 1859–1868 (1998).

    Article  CAS  Google Scholar 

  32. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270, 27489–27494 (1995).

    Article  CAS  Google Scholar 

  33. Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 269, 5241–5248 (1994).

    CAS  PubMed  Google Scholar 

  34. Powis, G. et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res. 54, 2419–2423 (1994).

    CAS  PubMed  Google Scholar 

  35. Smith, R. J. et al. Receptor-coupled signal transduction in human polymorphonuclear neutrophils: effects of a novel inhibitor of phospholipase C-dependent processes on cell responsiveness. J. Pharmacol. Exp.Ther. 253, 688–697 (1990).

    CAS  PubMed  Google Scholar 

  36. Gafni, J. et al. Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor. Neuron 19, 723–733 (1997).

    Article  CAS  Google Scholar 

  37. Ghosh, T. K., Eis, P. S., Mullaney, J. M., Ebert, C. L. & Gill, D. L. Competitive, reversible, and potent antagonism of inositol 1,4,5-trisphosphate-activated calcium release by heparin. J. Biol. Chem. 263, 11075–11079 (1988).

    CAS  PubMed  Google Scholar 

  38. Klippel, A. et al. Membrane localization of phosphatidylinositol 3-kinase is sufficient to activate multiple signal-transducing kinase pathways. Mol. Cell. Biol. 16, 4117–4127 (1996).

    Article  CAS  Google Scholar 

  39. Leissring, M. A., Parker, I. & LaFerla, F. M. Presenilin-2 mutations modulate amplitude and kinetics of inositol 1,4,5-trisphosphate-mediated calcium signals. J. Biol. Chem. 274, 32535–32538 (1999).

    Article  CAS  Google Scholar 

  40. Liou, H. C., Yang, R. S. & Fu, W. M. Potentiation of spontaneous acetylcholine release from motor nerve terminals by glutamate in Xenopus tadpoles. Neuroscience 75, 325–331 (1996).

    Article  CAS  Google Scholar 

  41. Dolcet, X., Egea, J., Soler, R. M., Martin-Zanca, D. & Comella, J. X. Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediate brain-derived neurotrophic factor-induced motoneuron survival. J. Neurochem. 73, 521–531 (1999).

    Article  CAS  Google Scholar 

  42. Lamballe, F., Klein, R. & Barbacid, M. TrkC, a new member of the Trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell 66, 967–979 (1991).

    Article  CAS  Google Scholar 

  43. Escandon, E. et al. Regulation of neurotrophin receptor expression during embryonic and postnatal development. J. Neurosci. 14, 2054–2068 (1994).

    Article  CAS  Google Scholar 

  44. Kokaia, M. et al. Endogenous neurotrophin-3 regulates short-term plasticity at lateral perforant path-granule cell synapses. J. Neurosci. 18, 8730–8739 (1998).

    Article  CAS  Google Scholar 

  45. Pettmann, B. & Henderson, C. E. Neuronal cell death. Neuron 20, 633–647 (1998).

    Article  CAS  Google Scholar 

  46. Kelly, A. & Lynch, M. A. Long-term potentiation in dentate gyrus of the rat is inhibited by the phosphoinositide 3-kinase inhibitor, wortmannin. Neuropharmacology 39, 643–651 (2000).

    Article  CAS  Google Scholar 

  47. Schiavo, G., Gu, Q. M., Prestwich, G. D., Sollner, T. H. & Rothman, J. E. Calcium-dependent switching of the specificity of phosphoinositide binding to synaptotagmin. Proc. Natl. Acad. Sci. USA 93, 13327–13332 (1996).

    Article  CAS  Google Scholar 

  48. Lu, B., Greengard, P. & Poo, M.-m. Exogenous synapsin I promotes functional maturation of developing neuromuscular synapses. Neuron 8, 521–529 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank L. Mei, S. Dudek and members of the Lu laboratory for discussions and comments on the manuscript, A. Klippel of Chiron for PI3K# and PI3K* cDNAs, and Regeneron Pharmaceuticals, Tarrytown, New York, for NT3.

Author information

Authors and Affiliations

  1. Unit on Synapse Development & Plasticity, Laboratory of Developmental Neurobiology, NICHD, NIH, Bethesda, 20892, Maryland, USA

    Feng Yang, Xiang-ping He, Linyin Feng, Keiko Mizuno, Xu-Wen Liu & Bai Lu

  2. Institutes of Neuroscience, Shanghai, 200031, China

    Linyin Feng

  3. Section on Cell Biology and Signal Transduction, Laboratory of Molecular and Cellular Neurophysiology, NICHD, NIH, Bethesda, 20892, Maryland, USA

    James Russell

  4. Department of Pathology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Wen-Cheng Xiong

Authors
  1. Feng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiang-ping He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linyin Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keiko Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xu-Wen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-Cheng Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bai Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bai Lu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, F., He, Xp., Feng, L. et al. PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation. Nat Neurosci 4, 19–28 (2001). https://doi.org/10.1038/82858

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/82858

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