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Synaptotagmin-IV modulates synaptic function and long-term potentiation by regulating BDNF release

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Abstract

Synaptotagmin-IV (syt-IV) is a membrane trafficking protein that influences learning and memory, but its localization and role in synaptic function remain unclear. We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. Syt-IV/BDNF–harboring vesicles underwent exocytosis in both axons and dendrites, and syt-IV inhibited BDNF release at both sites. Knockout of syt-IV increased, and overexpression decreased, the rate of synaptic vesicle exocytosis from presynaptic terminals indirectly via changes in postsynaptic release of BDNF. Thus, postsynaptic syt-IV regulates the trans-synaptic action of BDNF to control presynaptic vesicle dynamics. Furthermore, selective loss of presynaptic syt-IV increased spontaneous quantal release, whereas a loss of postsynaptic syt-IV increased quantal amplitude. Finally, syt-IV knockout mice showed enhanced long-term potentiation (LTP), which depended entirely on disinhibition of BDNF release. Thus, regulation of BDNF secretion by syt-IV emerges as a mechanism for maintaining synaptic strength in a useful range during LTP.

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Figure 1: Syt-IV is targeted to BDNF-containing vesicles.
Figure 2: Activity-induced syt-IV and BDNF colocalize and traffic together.
Figure 3: Syt-IV regulates BDNF release.
Figure 4: Depolarization induces syt-IV vesicle recycling in axons and dendrites.
Figure 5: Syt-IV inhibits regulated release of BDNF.
Figure 6: Syt-IV levels affect synaptic vesicle exocytosis.
Figure 7: Syt-IV modulates presynaptic function via regulation of postsynaptic BDNF release.
Figure 8: Syt-IV knockouts have enhanced LTP as a result of excess BDNF release.

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Change history

  • 28 May 2009

    In the version of this article initially published online, the yellow arrows in Figure 5a should be white arrowheads. Accordingly, the figure legend should read “(a) BDNF-pHluorin fluorescence decreased in dendrites (arrows) and increased in axons (arrowheads) following depolarization at t = 30 s.” These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M.-M. Poo and N. Matsuda for sharing their BDNF-pHluorin data with us and for comments on the manuscript, H. Herschman for providing the syt-IV knockout mice and members of the Chapman and Jackson laboratories for helpful discussions and comments on the manuscript. This work was supported by a US National Institutes of Health National Research Service Award to C.D. (NS049748), US National Institutes of Health grants to M.B.J. (NS30016 and NS44057) and to E.R.C. (National Institute of General Medical Sciences GM 56827 and National Institute of Mental Health MH61876), and American Heart Association (0440168N) grants to E.R.C. E.R.C. is an investigator of the Howard Hughes Medical Institute.

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C.D. designed and carried out the experiments, analyzed the data and wrote the paper. H.L. performed and analyzed mEPSC recordings. F.M.D constructed syt-IV fusion proteins. P.Y.C. wrote software for analysis of voltage imaging data. E.R.C. and M.B.J. supervised the project.

Corresponding authors

Correspondence to Camin Dean or Edwin R Chapman.

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Dean, C., Liu, H., Mark Dunning, F. et al. Synaptotagmin-IV modulates synaptic function and long-term potentiation by regulating BDNF release. Nat Neurosci 12, 767–776 (2009). https://doi.org/10.1038/nn.2315

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