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.

BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation

Abstract

The N-methyl-D-aspartate receptor (NMDAR), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95) and phosphatidylinositol 3-kinase (PI3K) have all been implicated in long-term potentiation. Here we show that these molecules are involved in a single pathway for synaptic potentiation. In visual cortical neurons in young rodents, the neurotrophin receptor TrkB is associated with PSD-95. When BDNF is applied to cultured visual cortical neurons, PSD-95–labeled synaptic puncta enlarge, and fluorescent recovery after photobleaching (FRAP) reveals increased delivery of green fluorescent protein–tagged PSD-95 to the dendrites. The recovery of fluorescence requires TrkB, signaling through PI3K and the serine-threonine kinase Akt, and an intact Golgi apparatus. Stimulation of NMDARs mimics the PSD-95 trafficking that is induced by BDNF but requires active BDNF and PI3K. Furthermore, local dendritic contact with a BDNF-coated microsphere induces PSD-95 FRAP throughout the dendrites of the stimulated neuron, suggesting that this mechanism induces rapid neuron-wide synaptic increases in PSD-95 and refinement whenever a few robust inputs activate the NMDAR-BDNF-PI3K pathway.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Full-length TrkB (TrkB-fl) selectively associates with PSD-95 in vivo.
Figure 2: Endogenous PSD-95 and TrkB-fl colocalize in vivo and in vitro.
Figure 3: BDNF treatment in vitro increases the size of PSD-95 puncta.
Figure 4: FRAP shows that dendritic transport of PSD-95 is facilitated by a pathway initiated by NMDAR stimulation of BDNF-TrkB signaling.
Figure 5: PSD-95–GFP FRAP but not SAP102-GFP FRAP is selective for BDNF and is independent of presynaptic effects or protein synthesis.
Figure 6: The facilitating effect of BDNF on PSD-95 FRAP is blocked by suppression of PI3K or Akt and by disruption of microtubule-based transport.
Figure 7: BDNF bead application to a short dendritic segment facilitates PSD-95–GFP FRAP throughout the dendritic tree of locally stimulated neurons.

References

  1. Kornau, H.C., Schenker, L.T., Kennedy, M.B. & Seeburg, P.H. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269, 1737–1740 (1995).

    CAS  Article  Google Scholar 

  2. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).

    CAS  Article  Google Scholar 

  3. Beique, J.C. & Andrade, R. PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J. Physiol. (Lond.) 546, 859–867 (2003).

    CAS  Article  Google Scholar 

  4. Stein, V., House, D.R., Bredt, D.S. & Nicoll, R.A. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression. J. Neurosci. 23, 5503–5506 (2003).

    CAS  Article  Google Scholar 

  5. Ehrlich, I. & Malinow, R. Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J. Neurosci. 24, 916–927 (2004).

    CAS  Article  Google Scholar 

  6. Kim, E. & Sheng, M. PDZ domain proteins of synapses. Nat. Rev. Neurosci. 5, 771–781 (2004).

    CAS  Article  Google Scholar 

  7. Yoshii, A., Sheng, M.H. & Constantine-Paton, M. Eye opening induces a rapid dendritic localization of PSD-95 in central visual neurons. Proc. Natl. Acad. Sci. USA 100, 1334–1339 (2003).

    CAS  Article  Google Scholar 

  8. Lu, W. & Constantine-Paton, M. Eye opening rapidly induces synaptic potentiation and refinement. Neuron 43, 237–249 (2004).

    CAS  Article  Google Scholar 

  9. Lessmann, V., Gottmann, K. & Malcangio, M. Neurotrophin secretion: current facts and future prospects. Prog. Neurobiol. 69, 341–374 (2003).

    CAS  Article  Google Scholar 

  10. Poo, M.M. Neurotrophins as synaptic modulators. Nat. Rev. Neurosci. 2, 24–32 (2001).

    CAS  Article  Google Scholar 

  11. Ji, Y., Pang, P.T., Feng, L. & Lu, B. Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Nat. Neurosci. 8, 164–172 (2005).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  13. Cabelli, R.J., Hohn, A. & Shatz, C.J. Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF. Science 267, 1662–1666 (1995).

    CAS  Article  Google Scholar 

  14. Huang, Z.J. et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739–755 (1999).

    CAS  Article  Google Scholar 

  15. Hanover, J.L., Huang, Z.J., Tonegawa, S. & Stryker, M.P. Brain-derived neurotrophic factor overexpression induces precocious critical period in mouse visual cortex. J. Neurosci. 19, RC40.1–RC40.5 (1999).

    Article  Google Scholar 

  16. Pang, P.T. et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306, 487–491 (2004).

    CAS  Article  Google Scholar 

  17. Du, J.L. & Poo, M.M. Rapid BDNF-induced retrograde synaptic modification in a developing retinotectal system. Nature 429, 878–883 (2004).

    CAS  Article  Google Scholar 

  18. Itami, C. et al. Brain-derived neurotrophic factor-dependent unmasking of “silent” synapses in the developing mouse barrel cortex. Proc. Natl. Acad. Sci. USA 100, 13069–13074 (2003).

    CAS  Article  Google Scholar 

  19. Kang, H. & Schuman, E.M. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267, 1658–1662 (1995).

    CAS  Article  Google Scholar 

  20. Figurov, A., Pozzo-Miller, L.D., 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).

    CAS  Article  Google Scholar 

  21. Kovalchuk, Y., Hanse, E., Kafitz, K.W. & Konnerth, A. Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295, 1729–1734 (2002).

    CAS  Article  Google Scholar 

  22. Suzuki, S. et al. BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts: roles in synaptic modulation. J. Cell Biol. 167, 1205–1215 (2004).

    CAS  Article  Google Scholar 

  23. Hering, H., Lin, C.C. & Sheng, M. Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J. Neurosci. 23, 3262–3271 (2003).

    CAS  Article  Google Scholar 

  24. Wu, K. et al. Functional trkB neurotrophin receptors are intrinsic components of the adult brain postsynaptic density. Brain Res. Mol. Brain Res. 43, 286–290 (1996).

    CAS  Article  Google Scholar 

  25. Sans, N. et al. A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J. Neurosci. 20, 1260–1271 (2000).

    CAS  Article  Google Scholar 

  26. Okabe, S., Urushido, T., Konno, D., Okado, H. & Sobue, K. Rapid redistribution of the postsynaptic density protein PSD-Zip45 (Homer 1c) and its differential regulation by NMDA receptors and calcium channels. J. Neurosci. 21, 9561–9571 (2001).

    CAS  Article  Google Scholar 

  27. Man, H.Y. et al. Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron 38, 611–624 (2003).

    CAS  Article  Google Scholar 

  28. Turner, T.J., Adams, M.E. & Dunlap, K. Calcium channels coupled to glutamate release identified by omega-Aga-IVA. Science 258, 310–313 (1992).

    CAS  Article  Google Scholar 

  29. Tang, S.J. et al. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. Natl. Acad. Sci. USA 99, 467–472 (2002).

    CAS  Article  Google Scholar 

  30. Vanhaesebroeck, B. et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535–602 (2001).

    CAS  Article  Google Scholar 

  31. Viard, P. et al. PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nat. Neurosci. 7, 939–946 (2004).

    CAS  Article  Google Scholar 

  32. Jaworski, J., Spangler, S., Seeburg, D.P., Hoogenraad, C.C. & Sheng, M. Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J. Neurosci. 25, 11300–11312 (2005).

    CAS  Article  Google Scholar 

  33. Kumar, V., Zhang, M.X., Swank, M.W., Kunz, J. & Wu, G.Y. Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J. Neurosci. 25, 11288–11299 (2005).

    CAS  Article  Google Scholar 

  34. Kau, T.R. et al. A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell 4, 463–476 (2003).

    CAS  Article  Google Scholar 

  35. Ma, D. et al. Role of ER export signals in controlling surface potassium channel numbers. Science 291, 316–319 (2001).

    CAS  Article  Google Scholar 

  36. El-Husseini Ael-D et al. Synaptic strength regulated by palmitate cycling on PSD-95. Cell 108, 849–863 (2002).

    CAS  Article  Google Scholar 

  37. Washbourne, P. Greasing transmission: palmitoylation at the synapse. Neuron 44, 901–902 (2004).

    CAS  PubMed  Google Scholar 

  38. Bhattacharyya, A. et al. Trk receptors function as rapid retrograde signal carriers in the adult nervous system. J. Neurosci. 17, 7007–7016 (1997).

    CAS  Article  Google Scholar 

  39. Penzes, P. et al. The neuronal Rho-GEF Kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis. Neuron 29, 229–242 (2001).

    CAS  Article  Google Scholar 

  40. Kang, H. & Schuman, E.M. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273, 1402–1406 (1996).

    CAS  Article  Google Scholar 

  41. Colledge, M. et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40, 595–607 (2003).

    CAS  Article  Google Scholar 

  42. Frey, U. & Morris, R.G. Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997).

    CAS  Article  Google Scholar 

  43. Alarcon, J.M., Barco, A. & Kandel, E.R. Capture of the late phase of long-term potentiation within and across the apical and basilar dendritic compartments of CA1 pyramidal neurons: synaptic tagging is compartment restricted. J. Neurosci. 26, 256–264 (2006).

    CAS  Article  Google Scholar 

  44. Martin, K.C. & Kosik, K.S. Synaptic tagging—who's it? Nat. Rev. Neurosci. 3, 813–820 (2002).

    CAS  Article  Google Scholar 

  45. Kwon, C.H. et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 50, 377–388 (2006).

    CAS  Article  Google Scholar 

  46. Chen, H.K. et al. Interaction of Akt-phosphorylated ataxin-1 with 14–3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113, 457–468 (2003).

    CAS  Article  Google Scholar 

  47. O'Kelly, I., Butler, M.H., Zilberberg, N. & Goldstein, S.A. Forward transport. 14–3-3 binding overcomes retention in endoplasmic reticulum by dibasic signals. Cell 111, 577–588 (2002).

    CAS  Article  Google Scholar 

  48. Michelsen, K., Yuan, H. & Schwappach, B. Hide and run. Arginine-based endoplasmic-reticulum-sorting motifs in the assembly of heteromultimeric membrane proteins. EMBO Rep. 6, 717–722 (2005).

    CAS  Article  Google Scholar 

  49. Banker, G. & Goslin, K. Culturing Nerve Cells (MIT Press, Cambridge, Massachusetts, USA, 1991).

  50. Parker, M.J. et al. PSD-93 regulates synaptic stability at neuronal cholinergic synapses. J. Neurosci. 24, 378–388 (2004).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank J. Hell for providing antibody to SAP102, D.E. Clapham and D.B. Arnold for permission to use the PSD-95–GFP construct, N. Sans and R. Wenthold for supplying the SAP102-GFP construct and E. Nedivi for comments on the manuscript. This work was supported by US National Institutes of Health grants RO1EY006039 and RO1EY014074.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Akira Yoshii.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Specificity of pan-TrkB antibody. (PDF 301 kb)

Supplementary Fig. 2

Whole-cell images of FRAP assay. (PDF 46666 kb)

Supplementary Fig. 3

Inhibition of Akt reduces PSD-95 Export to the Golgi. (PDF 6003 kb)

Supplementary Fig. 4

BDNF facilitates export of PSD-95 to the Golgi. (PDF 4181 kb)

Supplementary Fig. 5

Enlarged PSD-95-GFP puncta after application of a BDNF-coated bead. (PDF 602 kb)

Supplementary Fig. 6

A model for rapid, dendrite-wide, sensitization for synaptic potentiation conveyed by local NMDAR and BDNF activity-driven-PSD-95 trafficking to synapses throughout the neuron. (PDF 337 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yoshii, A., Constantine-Paton, M. BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation. Nat Neurosci 10, 702–711 (2007). https://doi.org/10.1038/nn1903

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1903

Further reading

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