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

Nature Neuroscience volume 10, pages 702–711 (2007)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139-4307, Massachusetts, USA

    Akira Yoshii & Martha Constantine-Paton

  2. Department of Brain and Cognitive Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139-4307, Massachusetts, USA

    Akira Yoshii & Martha Constantine-Paton

  3. McGovern Institute for Brain Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139-4307, Massachusetts, USA

    Akira Yoshii & Martha Constantine-Paton

  4. Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Akira Yoshii

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Correspondence to Akira Yoshii.

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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)

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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

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