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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
References
Chapman, E.R. How does synaptotagmin trigger neurotransmitter release? Annu. Rev. Biochem. 77, 615–641 (2008).
Koh, T.W. & Bellen, H.J. Synaptotagmin I, a Ca2+ sensor for neurotransmitter release. Trends Neurosci. 26, 413–422 (2003).
Bhalla, A., Tucker, W.C. & Chapman, E.R. Synaptotagmin isoforms couple distinct ranges of Ca2+, Ba2+ and Sr2+ concentration to SNARE-mediated membrane fusion. Mol. Biol. Cell 16, 4755–4764 (2005).
Hui, E. et al. Three distinct kinetic groupings of the synaptotagmin family: candidate sensors for rapid and delayed exocytosis. Proc. Natl. Acad. Sci. USA 102, 5210–5214 (2005).
Bhalla, A., Chicka, M.C. & Chapman, E.R. Analysis of the synaptotagmin family during reconstituted membrane fusion: uncovering a class of inhibitory isoforms. J. Biol. Chem. 283, 21799–21807 (2008).
Xu, J., Mashimo, T. & Sudhof, T.C. Synaptotagmin-1, -2 and -9: Ca2+ sensors for fast release that specify distinct presynaptic properties in subsets of neurons. Neuron 54, 567–581 (2007).
Vician, L. et al. Synaptotagmin IV is an immediate early gene induced by depolarization in PC12 cells and in brain. Proc. Natl. Acad. Sci. USA 92, 2164–2168 (1995).
Ibata, K., Fukuda, M., Hamada, T., Kabayama, H. & Mikoshiba, K. Synaptotagmin IV is present at the Golgi and distal parts of neurites. J. Neurochem. 74, 518–526 (2000).
Chapman, E.R., Desai, R.C., Davis, A.F. & Tornehl, C.K. Delineation of the oligomerization, AP-2 binding and synprint binding region of the C2B domain of synaptotagmin. J. Biol. Chem. 273, 32966–32972 (1998).
Wang, C.T. et al. Different domains of synaptotagmin control the choice between kiss-and-run and full fusion. Nature 424, 943–947 (2003).
Wang, C.T. et al. Synaptotagmin modulation of fusion pore kinetics in regulated exocytosis of dense-core vesicles. Science 294, 1111–1115 (2001).
Ahras, M., Otto, G.P. & Tooze, S.A. Synaptotagmin IV is necessary for the maturation of secretory granules in PC12 cells. J. Cell Biol. 173, 241–251 (2006).
Zhang, Q., Fukuda, M., Van Bockstaele, E., Pascual, O. & Haydon, P.G. Synaptotagmin IV regulates glial glutamate release. Proc. Natl. Acad. Sci. USA 101, 9441–9446 (2004).
Zhang, Z., Bhalla, A., Dean, C., Chapman, E.R. & Jackson, M.B. Synaptotagmin IV: a multifunctional regulator of peptidergic nerve terminals. Nat. Neurosci. 12, 163–171 (2009).
Osborne, S.L., Herreros, J., Bastiaens, P.I. & Schiavo, G. Calcium-dependent oligomerization of synaptotagmins I and II. Synaptotagmins I and II are localized on the same synaptic vesicle and heterodimerize in the presence of calcium. J. Biol. Chem. 274, 59–66 (1999).
Ting, J.T., Kelley, B.G. & Sullivan, J.M. Synaptotagmin IV does not alter excitatory fast synaptic transmission or fusion pore kinetics in mammalian CNS neurons. J. Neurosci. 26, 372–380 (2006).
Ibata, K. et al. Non-polarized distribution of synaptotagmin IV in neurons: evidence that synaptotagmin IV is not a synaptic vesicle protein. Neurosci. Res. 43, 401–406 (2002).
Berton, F. et al. Synaptotagmin I and IV define distinct populations of neuronal transport vesicles. Eur. J. Neurosci. 12, 1294–1302 (2000).
Littleton, J.T., Serano, T.L., Rubin, G.M., Ganetzky, B. & Chapman, E.R. Synaptic function modulated by changes in the ratio of synaptotagmin I and IV. Nature 400, 757–760 (1999).
Robinson, I.M., Ranjan, R. & Schwarz, T.L. Synaptotagmins I and IV promote transmitter release independently of Ca2+ binding in the C(2)A domain. Nature 418, 336–340 (2002).
Pawlu, C., DiAntonio, A. & Heckmann, M. Postfusional control of quantal current shape. Neuron 42, 607–618 (2004).
Yoshihara, M., Adolfsen, B., Galle, K.T. & Littleton, J.T. Retrograde signaling by Syt 4 induces presynaptic release and synapse-specific growth. Science 310, 858–863 (2005).
Ferguson, G.D., Anagnostaras, S.G., Silva, A.J. & Herschman, H.R. Deficits in memory and motor performance in synaptotagmin IV mutant mice. Proc. Natl. Acad. Sci. USA 97, 5598–5603 (2000).
Ferguson, G.D., Wang, H., Herschman, H.R. & Storm, D.R. Altered hippocampal short-term plasticity and associative memory in synaptotagmin IV (−/−) mice. Hippocampus 14, 964–974 (2004).
Denovan-Wright, E.M., Newton, R.A., Armstrong, J.N., Babity, J.M. & Robertson, H.A. Acute administration of cocaine, but not amphetamine, increases the level of synaptotagmin IV mRNA in the dorsal striatum of rat. Brain Res. Mol. Brain Res. 55, 350–354 (1998).
Peng, W. et al. Synaptotagmin I and IV are differentially regulated in the brain by the recreational drug 3,4-methylenedioxymethamphetamine (MDMA). Brain Res. Mol. Brain Res. 108, 94–101 (2002).
Poo, M.M. Neurotrophins as synaptic modulators. Nat. Rev. Neurosci. 2, 24–32 (2001).
Zemelman, B.V., Nesnas, N., Lee, G.A. & Miesenbock, G. Photochemical gating of heterologous ion channels: remote control over genetically designated populations of neurons. Proc. Natl. Acad. Sci. USA 100, 1352–1357 (2003).
Balkowiec, A. & Katz, D.M. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J. Neurosci. 22, 10399–10407 (2002).
Tyler, W.J. & Pozzo-Miller, L.D. BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J. Neurosci. 21, 4249–4258 (2001).
Tyler, W.J. et al. BDNF increases release probability and the size of a rapidly recycling vesicle pool within rat hippocampal excitatory synapses. J. Physiol. (Lond.) 574, 787–803 (2006).
Zakharenko, S.S. et al. Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1–CA3 synapses. Neuron 39, 975–990 (2003).
Chen, G., Kolbeck, R., Barde, Y.A., Bonhoeffer, T. & Kossel, A. Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation. J. Neurosci. 19, 7983–7990 (1999).
Kang, H., Welcher, A.A., Shelton, D. & Schuman, E.M. Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19, 653–664 (1997).
Rutherford, L.C., Nelson, S.B. & Turrigiano, G.G. BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses. Neuron 21, 521–530 (1998).
Chang, P.Y. & Jackson, M.B. Heterogeneous spatial patterns of long-term potentiation in hippocampal slices. J. Physiol. (Lond.) 576, 427–443 (2006).
Levine, E.S., Crozier, R.A., Black, I.B. & Plummer, M.R. Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-d-aspartic acid receptor activity. Proc. Natl. Acad. Sci. USA 95, 10235–10239 (1998).
Caldeira, M.V. et al. BDNF regulates the expression and the synaptic delivery of AMPA receptor subunits in hippocampal neurons. J. Biol. Chem. 282, 12619–12628 (2007).
Aicardi, G. et al. Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA 101, 15788–15792 (2004).
Aravanis, A.M., Pyle, J.L. & Tsien, R.W. Single synaptic vesicles fusing transiently and successively without loss of identity. Nature 423, 643–647 (2003).
Richards, D.A., Bai, J. & Chapman, E.R. Two modes of exocytosis at hippocampal synapses revealed by rate of FM1–43 efflux from individual vesicles. J. Cell Biol. 168, 929–939 (2005).
Kovalchuk, Y., Hanse, E., Kafitz, K.W. & Konnerth, A. Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295, 1729–1734 (2002).
Gärtner, A. et al. Hippocampal long-term potentiation is supported by presynaptic and postsynaptic tyrosine receptor kinase B-mediated phospholipase Cgamma signaling. J. Neurosci. 26, 3496–3504 (2006).
Perrais, D., Kleppe, I.C., Taraska, J.W. & Almers, W. Recapture after exocytosis causes differential retention of protein in granules of bovine chromaffin cells. J. Physiol. (Lond.) 560, 413–428 (2004).
Bohnert, S. & Schiavo, G. Tetanus toxin is transported in a novel neuronal compartment characterized by a specialized pH regulation. J. Biol. Chem. 280, 42336–42344 (2005).
Deinhardt, K. et al. Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52, 293–305 (2006).
Lu, Y., Christian, K. & Lu, B. BDNF: A key regulator for protein synthesis–dependent LTP and long-term memory? Neurobiol. Learn. Mem. 89, 312–323 (2008).
Shakiryanova, D., Tully, A. & Levitan, E.S. Activity-dependent synaptic capture of transiting peptidergic vesicles. Nat. Neurosci. 9, 896–900 (2006).
Tarsa, L. & Goda, Y. Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc. Natl. Acad. Sci. USA 99, 1012–1016 (2002).
Hartmann, M., Heumann, R. & Lessmann, V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J. 20, 5887–5897 (2001).
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.
Author information
Authors and Affiliations
Contributions
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
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6 (PDF 6885 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2315
This article is cited by
-
Neuroligin-1 mediates presynaptic maturation through brain-derived neurotrophic factor signaling
BMC Biology (2021)
-
Function of Drosophila Synaptotagmins in membrane trafficking at synapses
Cellular and Molecular Life Sciences (2021)
-
Alterations of transcriptome signatures in head trauma-related neurodegenerative disorders
Scientific Reports (2020)
-
The physiology of regulated BDNF release
Cell and Tissue Research (2020)
-
Journey of brain-derived neurotrophic factor: from intracellular trafficking to secretion
Cell and Tissue Research (2020)