Controversy exists regarding the site of modification of synaptic transmission during long-term plasticity in the mammalian hippocampus. Here we used a fluorescent marker of presynaptic activity, FM 1-43, to directly image changes in presynaptic function during both short-term and long-term forms of plasticity at presynaptic boutons of CA3–CA1 excitatory synapses in acute hippocampal slices. We demonstrated enhanced presynaptic function during long-term potentiation (LTP) induced either chemically (with tetraethylammonium), or by high-frequency (200-Hz) electrical stimulation. Both of these forms of LTP required activation of L-type voltage-gated calcium channels and NMDA receptors in the postsynaptic CA1 neuron. These results thus implied that a long-lasting increase in the efficacy of synaptic transmission is likely to depend, at least in part, on enhanced transmitter release from the presynaptic neuron.
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Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).
Milner, B., Squire, L. R. & Kandel, E. R. Cognitive neuroscience and the study of memory. Neuron 20, 445–468 (1998).
Bear, M. F. Homosynaptic long-term depression: a mechanism for memory? Proc. Natl. Acad. Sci. USA 96, 9457–9458 (1999).
Kullmann, D. M. & Siegelbaum, S. A. The site of expression of NMDA receptor-dependent LTP: new fuel for an old fire. Neuron 15, 997–1002 (1995).
Malenka, R. C. & Nicoll, R. A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999).
Malinow, R., Mainen, Z. F. & Hayashi, Y. LTP mechanisms: from silence to four-lane traffic. Curr. Opin. Neurobiol. 10, 352–357 (2000).
Shi, S. H. et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811–1816 (1999).
Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).
Carroll, R. C., Lissin, D. V., von Zastrow, M., Nicoll, R. A. & Malenka, R. C. Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures. Nat. Neurosci. 2, 454–460 (1999).
Luscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649–658 (1999).
Malinow, R. Transmission between pairs of hippocampal slice neurons: quantal levels, oscillations, and LTP. Science 252, 722–724 (1991).
Stevens, C. F. & Wang, Y. Changes in reliability of synaptic function as a mechanism for plasticity. Nature 371, 704–707 (1994).
Bolshakov, V. Y. & Siegelbaum, S. A. Regulation of hippocampal transmitter release during development and long-term potentiation. Science 269, 1730–1734 (1995).
Stricker, C., Cowan, A. I., Field, A. C. & Redman, S. J. Analysis of NMDA-independent long-term potentiation induced at CA3–CA1 synapses in rat hippocampus in vitro. J. Physiol. (Lond.) 520, 513–525 (1999).
Nicoll, R. A. & Malenka, R. C. Expression mechanisms underlying NMDA receptor-dependent long-term potentiation. Ann. NY Acad. Sci. 868, 515–525 (1999).
Betz, W. J. & Bewick, G. S. Optical analysis of synaptic vesicle recycling at the frog neuromuscular junction. Science 255, 200–203 (1992).
Ryan, T. A. et al. The kinetics of synaptic vesicle recycling measured at single presynaptic boutons. Neuron 11, 713–724 (1993).
Malgaroli, A. et al. Presynaptic component of long-term potentiation visualized at individual hippocampal synapses. Science 268, 1624–1628 (1995).
Ryan, T. A., Ziv, N. E. & Smith, S. J. Potentiation of evoked vesicle turnover at individually resolved synaptic boutons. Neuron 17, 125–134 (1996).
Ma, L., Zablow, L., Kandel, E. R. & Siegelbaum, S. A. Cyclic AMP induces functional presynaptic boutons in hippocampal CA3–CA1 neuronal cultures. Nat. Neurosci. 2, 24–30 (1999).
Denk, W., Strickler, J. H. & Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990).
Mainen, Z. F. et al. Two-photon imaging in living brain slices. Methods 18, 231–239 (1999).
Kay, A. R. et al. Imaging synaptic activity in intact brain and slices with FM1-43 in C. elegans, lamprey, and rat. Neuron 24, 809–817 (1999).
Hiscock, J. J., Murphy, S. & Willoughby, J. O. Confocal microscopic estimation of GABAergic nerve terminals in the central nervous system. J. Neurosci. Methods 95, 1–11 (2000).
Maletic-Savatic, M., Koothan, T. & Malinow, R. Calcium-evoked dendritic exocytosis in cultured hippocampal neurons. Part II: mediation by calcium/calmodulin-dependent protein kinase II. J. Neurosci. 18, 6814–6821 (1998).
Liu, G. & Tsien, R. W. Properties of synaptic transmission at single hippocampal synaptic boutons. Nature 375, 404–408 (1995).
Stevens, C. F. & Tsujimoto, T. Estimates for the pool size of releasable quanta at a single central synapse and for the time required to refill the pool. Proc. Natl. Acad. Sci. USA 92, 846–849 (1995).
Klingauf, J., Kavalali, E. T. & Tsien, R. W. Kinetics and regulation of fast endocytosis at hippocampal synapses. Nature 394, 581–585 (1998).
Harris, K. M. & Stevens, J. K. Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J. Neurosci. 9, 2982–2997 (1989).
Murthy, V. N., Sejnowski, T. J. & Stevens, C. F. Heterogeneous release properties of visualized individual hippocampal synapses. Neuron 18, 599–612 (1997).
Rosenmund, C. & Stevens, C. F. Definition of the readily releasable pool of vesicles at hippocampal synapses. Neuron 16, 1197–1207 (1996).
Ryan, T. A. & Smith, S. J. Vesicle pool mobilization during action potential firing at hippocampal synapses. Neuron 14, 983–989 (1995).
Dunwiddie, T. V., Hoffer, B. J. & Fredholm, B. B. Alkylxanthines elevate hippocampal excitability. Evidence for a role of endogenous adenosine. Naunyn Schmiedebergs Arch. Pharmacol. 316, 326–330 (1981).
Cunha, R. A. & Ribeiro, J. A. Purinergic modulation of [(3)H]GABA release from rat hippocampal nerve terminals. Neuropharmacology 39, 1156–1167 (2000).
Lambert, N. A. & Teyler, T. J. Adenosine depresses excitatory but not fast inhibitory synaptic transmission in area CA1 of the rat hippocampus. Neurosci. Lett. 122, 50–52 (1991).
Yoon, K. W. & Rothman, S. M. Adenosine inhibits excitatory but not inhibitory synaptic transmission in the hippocampus. J. Neurosci. 11, 1375–1380 (1991).
Stevens, C. F. & Wang, Y. Facilitation and depression at single central synapses. Neuron 14, 795–802 (1995).
Aniksztejn, L. & Ben-Ari, Y. Novel form of long-term potentiation produced by a K+ channel blocker in the hippocampus. Nature 349, 67–69 (1991).
Huang, Y. Y. & Malenka, R. C. Examination of TEA-induced synaptic enhancement in area CA1 of the hippocampus: the role of voltage-dependent Ca2+ channels in the induction of LTP. J. Neurosci. 13, 568–576 (1993).
Grover, L. M. & Teyler, T. J. Two components of long-term potentiation induced by different patterns of afferent activation. Nature 347, 477–479 (1990).
Hanse, E. & Gustafsson, B. TEA elicits two distinct potentiations of synaptic transmission in the CA1 region of the hippocampal slice. J. Neurosci. 14, 5028–5034 (1994).
Harris, E. W., Ganong, A. H. & Cotman, C. W. Long-term potentiation in the hippocampus involves activation of N- methyl-D-aspartate receptors. Brain Res. 323, 132–137 (1984).
Hawkins, R. D., Son, H. & Arancio, O. Nitric oxide as a retrograde messenger during long-term potentiation in hippocampus. Prog. Brain Res. 118, 155–172 (1998).
Choi, S., Klingauf, J. & Tsien, R. W. Postfusional regulation of cleft glutamate concentration during LTP at 'silent synapses.' Nat. Neurosci. 3, 330–306 (2000).
Toni, N., Buchs, P. A., Nikonenko, I., Bron, C. R. & Muller, D. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999).
Bozdagi, O., Shan, W., Tanaka, H., Benson, D. L. & Huntley, G. W. Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron 28, 245–259 (2000).
Huang, Y. Y., Nguyen, P. V., Abel, T. & Kandel, E. R. Long-lasting forms of synaptic potentiation in the mammalian hippocampus. Learn. Mem. 3, 74–85 (1996).
Schuman, E. M. & Madison, D. V. Locally distributed synaptic potentiation in the hippocampus. Science 263, 532–536 (1994).
Engert, F. & Bonhoeffer, T. Synapse specificity of long-term potentiation breaks down at short distances. Nature 388, 279–284 (1997).
We thank R. Hawkins, E. Kandel, M. Nolan, S. Patterson and V. Unni for comments on the manuscript, and E. Odell for help with artwork. This work was partially supported by a grant from the NIH.
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Zakharenko, S., Zablow, L. & Siegelbaum, S. Visualization of changes in presynaptic function during long-term synaptic plasticity. Nat Neurosci 4, 711–717 (2001). https://doi.org/10.1038/89498
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