Silent synapses, which cannot mediate neurotransmission because they lack functional AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), were discovered in the hippocampal CA1 subfield amidst the debate over whether long-term potentiation (LTP) resulted from a presynaptic or a postsynaptic modification. Their existence helped to explain what had seemed to be contradictory findings regarding the locus of LTP expression.
Silent synapses — which are found not only in the hippocampus but also in many areas of the brain and spinal cord — exhibit a developmental gradient, declining in prevalence over the first few days to weeks of life in rodents.
Synapse unsilencing occurs when coordinated pre- and postsynaptic activity — as encountered during an LTP induction protocol — results in the activation of NMDARs (N-methyl-D-aspartate receptors) and the subsequent recruitment of AMPARs to the postsynaptic membrane. Synapse unsilencing is a mechanism of LTP expression.
Some groups have proposed that synaptic silence may result from slow glutamate diffusion rather than from absent AMPARs. Glutamate spillover from adjacent synapses and impaired release from an immature presynaptic terminal are two models discussed.
However, the preponderance of evidence favours the hypothesis that synaptic silence results instead from the physical absence of functional AMPARs at the postsynaptic membrane. Glutamate uncaging experiments have provided the most-direct, unequivocal evidence that LTP and synaptic silence occur by a postsynaptic mechanism.
This characterization of silent synapses has culminated in a general acceptance that the movement of AMPARs into and out of synapses accounts for excitatory synaptic plasticity. The next challenge is to identify the molecular underpinnings of AMPAR trafficking.
Silent synapses abound in the young brain, representing an early step in the pathway of experience-dependent synaptic development. Discovered amidst the debate over whether long-term potentiation reflects a presynaptic or a postsynaptic modification, silent synapses — which in the hippocampal CA1 subfield are characterized by the presence of NMDA receptors but not AMPA receptors — have stirred some mechanistic controversy of their own. Out of this literature has emerged a model for synapse unsilencing that highlights the central role for postsynaptic AMPA-receptor trafficking in the expression of excitatory synaptic plasticity.
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Malenka, R. C., Kauer, J. A., Perkel, D. J. & Nicoll, R. A. The impact of postsynaptic calcium on synaptic transmission — its role in long-term potentiation. Trends Neurosci. 12, 444–450 (1989).
Liao, D., Hessler, N. A. & Malinow, R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 (1995). This paper and reference 3, which was published two months later, first established the presence of hippocampal CA1 silent synapses. Both groups used a minimal-stimulation technique to isolate synapses exhibiting the (now classic) physiological signature of a silent synapse — the presence of N-EPSCs but not A-EPSCs — and both groups went on to show that LTP triggered the rapid recruitment of an AMPAR-mediated response.
Isaac, J. T., Nicoll, R. A. & Malenka, R. C. Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427–434 (1995).
Merrill, E. G. & Wall, P. D. Factors forming the edge of a receptive field: the presence of relatively ineffective afferent terminals. J. Physiol. 226, 825–846 (1972).
Wall, P. D. The presence of ineffective synapses and the circumstances which unmask them. Philos. Trans. R. Soc. Lond. B Biol. Sci. 278, 361–372 (1977).
Malenka, R. C. & Nicoll, R. A. Silent synapses speak up. Neuron 19, 473–476 (1997).
Redman, S. Quantal analysis of synaptic potentials in neurons of the central nervous system. Physiol. Rev. 70, 165–198 (1990).
Kerchner, G. A., Li, P. & Zhuo, M. Speaking out of turn: a role for silent synapses in pain. IUBMB Life 48, 251–256 (1999).
Faber, D. S., Lin, J. W. & Korn, H. Silent synaptic connections and their modifiability. Ann. NY Acad. Sci. 627, 151–164 (1991).
Charpier, S., Behrends, J. C., Triller, A., Faber, D. S. & Korn, H. “Latent” inhibitory connections become functional during activity-dependent plasticity. Proc. Natl Acad. Sci. USA 92, 117–120 (1995).
Wolszon, L. & Faber, D. The effects of postsynaptic levels of cyclic AMP on excitatory and inhibitory responses of an identified central neuron. J. Neurosci. 9, 784–797 (1989).
Lin, J. W. & Faber, D. S. Synaptic transmission mediated by single club endings on the goldfish Mauthner cell. II. Plasticity of excitatory postsynaptic potentials. J. Neurosci. 8, 1313–1325 (1988).
Lin, J. W. & Faber, D. S. Synaptic transmission mediated by single club endings on the goldfish Mauthner cell. I. Characteristics of electrotonic and chemical postsynaptic potentials. J. Neurosci. 8, 1302–1312 (1988).
Wojtowicz, J. M., Marin, L. & Atwood, H. L. Activity-induced changes in synaptic release sites at the crayfish neuromuscular junction. J. Neurosci. 14, 3688–3703 (1994).
Wojtowicz, J. M., Smith, B. R. & Atwood, H. L. Activity-dependent recruitment of silent synapses. Ann. NY Acad. Sci. 627, 169–179 (1991).
Stevens, C. F. Quantal release of neurotransmitter and long-term potentiation. Cell 72, 55–63 (1993).
Nicoll, R. A. & Malenka, R. C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377, 115–118 (1995).
Kauer, J. A., Malenka, R. C. & Nicoll, R. A. A persistent postsynaptic modification mediates long-term potentiation in the hippocampus. Neuron 1, 911–917 (1988).
Muller, D., Joly, M. & Lynch, G. Contributions of quisqualate and NMDA receptors to the induction and expression of LTP. Science 242, 1694–1697 (1988).
Muller, D. & Lynch, G. Long-term potentiation differentially affects two components of synaptic responses in hippocampus. Proc. Natl Acad. Sci. USA 85, 9346–9350 (1988).
Kullmann, D. M. Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: implications for long-term potentiation. Neuron 12, 1111–1120 (1994). As one of the last milestones in the journey that ultimately led to the discovery of silent synapses in the hippocampus, this study elegantly illustrated that the quantal content for N-EPSCs is paradoxically different from the quantal content for A-EPSCs, and that only the latter changes during LTP. Kullmann proposed that LTP-induced uncovering of latent AMPAR clusters could explain this finding, in the absence of any change in presynaptic glutamate release.
Bekkers, J. M. & Stevens, C. F. NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature 341, 230–233 (1989).
Patneau, D. K. & Mayer, M. L. Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-D-aspartate and quisqualate receptors. J. Neurosci. 10, 2385–2399 (1990).
Perkel, D. J. & Nicoll, R. A. Evidence for all-or-none regulation of neurotransmitter release: implications for long-term potentiation. J. Physiol. 471, 481–500 (1993).
Tong, G. & Jahr, C. E. Multivesicular release from excitatory synapses of cultured hippocampal neurons. Neuron 12, 51–59 (1994).
Choi, S., Klingauf, J. & Tsien, R. W. Postfusional regulation of cleft glutamate concentration during LTP at 'silent synapses'. Nature Neurosci. 3, 330–336 (2000).
Asztely, F., Wigstrom, H. & Gustafsson, B. The relative contribution of NMDA receptor channels in the expression of long-term potentiation in the hippocampal CA1 region. Eur. J. Neurosci. 4, 681–690 (1992).
Gustafsson, B., Huang, Y. Y. & Wigstrom, H. Phorbol ester-induced synaptic potentiation differs from long-term potentiation in the guinea pig hippocampus in vitro. Neurosci. Lett. 85, 77–81 (1988).
Malinow, R. & Tsien, R. W. Presynaptic enhancement shown by whole-cell recordings of long-term potentiation in hippocampal slices. Nature 346, 177–180 (1990). This paper was groundbreaking for two reasons: first, it marked the first time that LTP was induced in a hippocampal slice by a pairing protocol during whole-cell patch-clamp recording; and second, because the signal-to-noise ratio of this technique is superior to that of intracellular sharp-electrode recordings, the authors could perform quantal analysis on EPSCs evoked by minimal stimulation and demonstrate an increase in quantal content and a decrease in synaptic failures following LTP.
Bekkers, J. M. & Stevens, C. F. Presynaptic mechanism for long-term potentiation in the hippocampus. Nature 346, 724–729 (1990). Published a month after reference 29, this paper yielded similar findings.
Voronin, L. L. Long-term potentiation in the hippocampus. Neuroscience 10, 1051–1069 (1983).
Bolshakov, V. Y. & Siegelbaum, S. A. Regulation of hippocampal transmitter release during development and long-term potentiation. Science 269, 1730–1734 (1995).
Stevens, C. F. & Wang, Y. Changes in reliability of synaptic function as a mechanism for plasticity. Nature 371, 704–707 (1994).
Kullmann, D. M. & Nicoll, R. A. Long-term potentiation is associated with increases in quantal content and quantal amplitude. Nature 357, 240–244 (1992).
Liao, D., Jones, A. & Malinow, R. Direct measurement of quantal changes underlying long-term potentiation in CA1 hippocampus. Neuron 9, 1089–1097 (1992).
Larkman, A., Hannay, T., Stratford, K. & Jack, J. Presynaptic release probability influences the locus of long-term potentiation. Nature 360, 70–73 (1992).
Stricker, C., Field, A. C. & Redman, S. J. Changes in quantal parameters of EPSCs in rat CA1 neurones in vitro after the induction of long-term potentiation. J. Physiol. 490, 443–454 (1996).
Edwards, F. A., Konnerth, A. & Sakmann, B. Quantal analysis of inhibitory synaptic transmission in the dentate gyrus of rat hippocampal slices: a patch-clamp study. J. Physiol. 430, 213–249 (1990).
Edwards, F. LTP is a long term problem. Nature 350, 271–272 (1991).
Larkman, A., Stratford, K. & Jack, J. Quantal analysis of excitatory synaptic action and depression in hippocampal slices. Nature 350, 344–347 (1991).
Faber, D. S. & Korn, H. Applicability of the coefficient of variation method for analyzing synaptic plasticity. Biophys. J. 60, 1288–1294 (1991).
Liu, G., Choi, S. & Tsien, R. W. Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices. Neuron 22, 395–409 (1999).
Mainen, Z. F., Malinow, R. & Svoboda, K. Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature 399, 151–155 (1999).
Pankratov, Y. V. & Krishtal, O. A. Distinct quantal features of AMPA and NMDA synaptic currents in hippocampal neurons: implication of glutamate spillover and receptor saturation. Biophys. J. 85, 3375–3387 (2003).
Malinow, R. Transmission between pairs of hippocampal slice neurons: quantal levels, oscillations, and LTP. Science 252, 722–724 (1991).
Manabe, T., Wyllie, D. J., Perkel, D. J. & Nicoll, R. A. Modulation of synaptic transmission and long-term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus. J. Neurophysiol. 70, 1451–1459 (1993).
Kullmann, D. M., Erdemli, G. & Asztély, F. LTP of AMPA and NMDA receptor-mediated signals: evidence for presynaptic expression and extrasynaptic glutamate spill-over. Neuron 17, 461–474 (1996).
Collingridge, G. L. Long-term potentiation. A question of reliability. Nature 371, 652–653 (1994).
Lisman, J. E. & Harris, K. M. Quantal analysis and synaptic anatomy — integrating two views of hippocampal plasticity. Trends Neurosci. 16, 141–147 (1993).
Wu, G., Malinow, R. & Cline, H. T. Maturation of a central glutamatergic synapse. Science 274, 972–976 (1996).
Lledo, P. M. et al. Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proc. Natl Acad. Sci. USA 92, 11175–11179 (1995).
Hsia, A. Y., Malenka, R. C. & Nicoll, R. A. Development of excitatory circuitry in the hippocampus. J. Neurophysiol. 79, 2013–2024 (1998).
Liao, D. & Malinow, R. Deficiency in induction but not expression of LTP in hippocampal slices from young rats. Learn. Mem. 3, 138–149 (1996).
Durand, G. M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996). Another early demonstration of silent CA1 synapses (see also references 2 and 3), this paper was the first to provide an explicit analysis of the developmental time course of their expression.
Rumpel, S., Kattenstroth, G. & Gottmann, K. Silent synapses in the immature visual cortex: layer-specific developmental regulation. J. Neurophysiol. 91, 1097–1101 (2004).
Adesnik, H., Li, G., During, M. J., Pleasure, S. J. & Nicoll, R. A. NMDA receptors inhibit synapse unsilencing during brain development. Proc. Natl Acad. Sci. USA 105, 5597–5602 (2008).
Hall, B. J. & Ghosh, A. Regulation of AMPA receptor recruitment at developing synapses. Trends Neurosci. 31, 82–89 (2008).
Hall, B. J., Ripley, B. & Ghosh, A. NR2B signaling regulates the development of synaptic AMPA receptor current. J. Neurosci. 27, 13446–13456 (2007).
Luthi, A., Schwyzer, L., Mateos, J. M., Gahwiler, B. H. & McKinney, R. A. NMDA receptor activation limits the number of synaptic connections during hippocampal development. Nature Neurosci. 4, 1102–1107 (2001).
Xiao, M. Y., Wasling, P., Hanse, E. & Gustafsson, B. Creation of AMPA-silent synapses in the neonatal hippocampus. Nature Neurosci. 7, 236–243 (2004).
Abrahamsson, T., Gustafsson, B. & Hanse, E. Reversible synaptic depression in developing rat CA3–CA1 synapses explained by a novel cycle of AMPA silencing-unsilencing. J. Neurophysiol. 98, 2604–2611 (2007).
Montgomery, J. M. & Madison, D. V. State-dependent heterogeneity in synaptic depression between pyramidal cell pairs. Neuron 33, 765–777 (2002).
Gasparini, S., Saviane, C., Voronin, L. L. & Cherubini, E. Silent synapses in the developing hippocampus: lack of functional AMPA receptors or low probability of glutamate release? Proc. Natl Acad. Sci. USA 97, 9741–9746 (2000).
Maggi, L., Le Magueresse, C., Changeux, J. P. & Cherubini, E. Nicotine activates immature “silent” connections in the developing hippocampus. Proc. Natl Acad. Sci. USA 100, 2059–2064 (2003).
Montgomery, J. M., Pavlidis, P. & Madison, D. V. Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation. Neuron 29, 691–701 (2001). By simultaneously patch-clamping both the pre- and the postsynaptic neurons during recordings of silent synapses, these authors achieved a level of experimental control superior to contemporary methods of minimal extracellular stimulation and refuted many of the arguments for a presynaptic mechanism for synaptic silence.
Kullmann, D. M. & Asztely, F. Extrasynaptic glutamate spillover in the hippocampus: evidence and implications. Trends Neurosci. 21, 8–14 (1998).
Selig, D. K., Hjelmstad, G. O., Herron, C., Nicoll, R. A. & Malenka, R. C. Independent mechanisms for long-term depression of AMPA and NMDA responses. Neuron 15, 417–426 (1995).
Manabe, T. & Nicoll, R. A. Long-term potentiation: evidence against an increase in transmitter release probability in the CA1 region of the hippocampus. Science 265, 1888–1892 (1994).
Diamond, J. S. Neuronal glutamate transporters limit activation of NMDA receptors by neurotransmitter spillover on CA1 pyramidal cells. J. Neurosci. 21, 8328–8338 (2001).
Diamond, J. S. A broad view of glutamate spillover. Nature Neurosci. 5, 291–292 (2002).
Arnth-Jensen, N., Jabaudon, D. & Scanziani, M. Cooperation between independent hippocampal synapses is controlled by glutamate uptake. Nature Neurosci. 5, 325–331 (2002).
Lozovaya, N. A., Kopanitsa, M. V., Boychuk, Y. A. & Krishtal, O. A. Enhancement of glutamate release uncovers spillover-mediated transmission by N-methyl-D-aspartate receptors in the rat hippocampus. Neuroscience 91, 1321–1330 (1999).
Diamond, J. S., Bergles, D. E. & Jahr, C. E. Glutamate release monitored with astrocyte transporter currents during LTP. Neuron 21, 425–433 (1998). This paper, together with reference 74 (published back-to-back in the same issue), established that the magnitude of a glutamate-transporter current in CA1 astrocytes is a reliable surrogate for synaptic glutamate concentration, and that this concentration does not change after LTP.
Lüscher, C., Malenka, R. C. & Nicoll, R. A. Monitoring glutamate release during LTP with glial transporter currents. Neuron 21, 435–441 (1998).
Renger, J. J., Egles, C. & Liu, G. A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation. Neuron 29, 469–484 (2001).
Arancio, O. et al. Nitric oxide acts directly in the presynaptic neuron to produce long-term potentiation in cultured hippocampal neurons. Cell 87, 1025–1035 (1996).
Schuman, E. M. & Madison, D. V. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 254, 1503–1506 (1991).
Son, H. et al. Long-term potentiation is reduced in mice that are doubly mutant in endothelial and neuronal nitric oxide synthase. Cell 87, 1015–1023 (1996).
Cummings, J. A., Nicola, S. M. & Malenka, R. C. Induction in the rat hippocampus of long-term potentiation (LTP) and long-term depression (LTD) in the presence of a nitric oxide synthase inhibitor. Neurosci. Lett. 176, 110–114 (1994).
Selig, D. K. et al. Examination of the role of cGMP in long-term potentiation in the CA1 region of the hippocampus. Learn. Mem. 3, 42–48 (1996).
Serulle, Y. et al. A GluR1-cGKII interaction regulates AMPA receptor trafficking. Neuron 56, 670–688 (2007).
Nicoll, R. A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nature Rev. Neurosci. 6, 863–876 (2005).
Zalutsky, R. A. & Nicoll, R. A. Comparison of two forms of long-term potentiation in single hippocampal neurons. Science 248, 1619–1624 (1990).
Tong, G., Malenka, R. C. & Nicoll, R. A. Long-term potentiation in cultures of single hippocampal granule cells: a presynaptic form of plasticity. Neuron 16, 1147–1157 (1996).
Debanne, D., Gahwiler, B. H. & Thompson, S. M. Long-term synaptic plasticity between pairs of individual CA3 pyramidal cells in rat hippocampal slice cultures. J. Physiol. 507, 237–247 (1998).
Gomperts, S. N., Rao, A., Craig, A. M., Malenka, R. C. & Nicoll, R. A. Postsynaptically silent synapses in single neuron cultures. Neuron 21, 1443–1451 (1998).
Ward, B. et al. State-dependent mechanisms of LTP expression revealed by optical quantal analysis. Neuron 52, 649–661 (2006).
Zakharenko, S. S., Zablow, L. & Siegelbaum, S. A. Visualization of changes in presynaptic function during long-term synaptic plasticity. Nature Neurosci. 4, 711–717 (2001).
Liao, D., Zhang, X., O'Brien, R., Ehlers, M. D. & Huganir, R. L. Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons. Nature Neurosci. 2, 37–43 (1999).
Richmond, S. A. et al. Localization of the glutamate receptor subunit GluR1 on the surface of living and within cultured hippocampal neurons. Neuroscience 75, 69–82 (1996).
Pickard, L., Noel, J., Henley, J. M., Collingridge, G. L. & Molnar, E. Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons. J. Neurosci. 20, 7922–7931 (2000).
Liao, D., Scannevin, R. H. & Huganir, R. Activation of silent synapses by rapid activity-dependent synaptic recruitment of AMPA receptors. J. Neurosci. 21, 6008–6017 (2001).
Lu, W.-Y. et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001).
Pickard, L. et al. Transient synaptic activation of NMDA receptors leads to the insertion of native AMPA receptors at hippocampal neuronal plasma membranes. Neuropharmacology 41, 700–713 (2001).
Nusser, Z. et al. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21, 545–559 (1998).
Petralia, R. S. et al. Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nature Neurosci. 2, 31–36 (1999).
Racca, C., Stephenson, F. A., Streit, P., Roberts, J. D. B. & Somogyi, P. NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J. Neurosci. 20, 2512–2522 (2000).
Takumi, Y., Ramirez-Leon, V., Laake, P., Rinvik, E. & Ottersen, O. P. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nature Neurosci. 2, 618–624 (1999).
Bagal, A. A., Kao, J. P., Tang, C. M. & Thompson, S. M. Long-term potentiation of exogenous glutamate responses at single dendritic spines. Proc. Natl Acad. Sci. USA 102, 14434–14439 (2005).
Busetto, G., Higley, M. J. & Sabatini, B. L. Developmental presence and disappearance of postsynaptically silent synapses on dendritic spines of rat layer 2/3 pyramidal neurons. J. Physiol. 586, 1519–1527 (2008). By using glutamate uncaging to trigger uEPSCs and thus to bypass the presynaptic terminal, this paper was the first to demonstrate unequivocally that silent synapses express no functional AMPARs in the postsynaptic membrane.
Harvey, C. D. & Svoboda, K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature 450, 1195–1200 (2007).
Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nature Neurosci. 4, 1086–1092 (2001).
Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. R. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004). This paper was the first to induce LTP at single spines through repetitive glutamate uncaging. It demonstrated conclusively that LTP could occur by a purely postsynaptic mechanism.
Zhang, Y.-P., Holbro, N. & Oertner, T. G. Optical induction of plasticity at single synapses reveals input-specific accumulation of αCaMKII. Proc. Natl Acad. Sci. USA 105, 12039–12044 (2008).
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).
Shi, S.-H. et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811–1816 (1999). In hippocampal neurons that expressed a recombinant GluR1 AMPAR subunit tagged with GFP, these authors observed rapid delivery of tagged receptors to the postsynaptic membrane from intracellular stores following LTP induction, providing evidence that LTP occurs by trafficking AMPARs to synapses.
Adesnik, H., Nicoll, R. A. & England, P. M. Photoinactivation of native AMPA receptors reveals their real-time trafficking. Neuron 48, 977–985 (2005).
Lynch, G. & Baudry, M. The biochemistry of memory: a new and specific hypothesis. Science 224, 1057–1063 (1984).
Wang, R. et al. TARP proteins have fundamental roles in the gating of glutamate receptors and the tuning of synaptic function. Neuron (in the press).
Walker, C. S. et al. Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins. Proc. Natl Acad. Sci. USA 103, 10781–10786 (2006).
Nicoll, R. A., Tomita, S. & Bredt, D. S. Auxiliary subunits assist AMPA-type glutamate receptors. Science 311, 1253–1256 (2006).
Manabe, T., Renner, P. & Nicoll, R. A. Postsynaptic contribution to long-term potentiation revealed by the analysis of miniature synaptic currents. Nature 355, 50–55 (1992).
Isaac, J. T., Hjelmstad, G. O., Nicoll, R. A. & Malenka, R. C. Long-term potentiation at single fiber inputs to hippocampal CA1 pyramidal cells. Proc. Natl Acad. Sci. USA 93, 8710–8715 (1996).
Oliet, S. H., Malenka, R. C. & Nicoll, R. A. Bidirectional control of quantal size by synaptic activity in the hippocampus. Science 271, 1294–1297 (1996).
Benke, T. A., Luthi, A., Isaac, J. T. R. & Collingridge, G. L. Modulation of AMPA receptor unitary conductance by synaptic activity. Nature 393, 793–797 (1998).
Andrásfalvy, B. K. & Magee, J. C. Changes in AMPA receptor currents following LTP induction on rat CA1 pyramidal neurons. J. Physiol. 559, 543–554 (2004).
Bredt, D. S. & Nicoll, R. A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).
Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).
Song, I. & Huganir, R. L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 25, 578–588 (2002).
Emptage, N. J., Reid, C. A., Fine, A. & Bliss, T. V. P. Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses. Neuron 38, 797–804 (2003).
Ramón y Cajal, S. Histologie du Système Nerveux de l'Homme et des Vertébrés (Maloine, Paris, 1909).
Isaac, J. T., Crair, M. C., Nicoll, R. A. & Malenka, R. C. Silent synapses during development of thalamocortical inputs. Neuron 18, 269–280 (1997).
Blakemore, C. & Hillman, P. An attempt to assess the effects of monocular deprivation and strabismus on synaptic efficiency in the kitten's visual cortex. Exp. Brain Res. 30, 187–202 (1977).
Rumpel, S., Hatt, H. & Gottmann, K. Silent synapses in the developing rat visual cortex: evidence for postsynaptic expression of synaptic plasticity. J. Neurosci. 18, 8863–8874 (1998).
Shah, R. D. & Crair, M. C. Retinocollicular synapse maturation and plasticity are regulated by correlated retinal waves. J. Neurosci. 28, 292–303 (2008).
Losi, G., Prybylowski, K., Fu, Z., Luo, J. H. & Vicini, S. Silent synapses in developing cerebellar granule neurons. J. Neurophysiol. 87, 1263–1270 (2002).
Balland, B., Lachamp, P., Kessler, J.-P. & Tell, F. Silent synapses in developing rat nucleus tractus solitarii have AMPA receptors. J. Neurosci. 28, 4624–4634 (2008).
Lo, F.-S. & Erzurumlu, R. S. Conversion of functional synapses into silent synapses in the trigeminal brainstem after neonatal peripheral nerve transection. J. Neurosci. 27, 4929–4934 (2007).
Park, M., Penick, E. C., Edwards, J. G., Kauer, J. A. & Ehlers, M. D. Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972–1975 (2000).
We thank A. Jackson, W. Lu, A. Milstein and A. Tzingounis for their thoughtful comments on the manuscript. R.A.N. is supported by grants from the US National Institutes of Health and G.A.K. was supported by the Larry L. Hillblom Foundation.
The area of the hippocampus that lies at the end of the hippocampal trisynaptic circuit.
- Silent synapse
Aside from the exceptions indicated in this Review, silent synapses are synapses that exhibit an NMDA-receptor-mediated response but no AMPA-receptor-mediated response.
- Excitatory postsynaptic current
(EPSC). The current that is recorded in a voltage-clamped neuron in response to release of synaptic glutamate.
(N-methyl-D-aspartate receptor). The subtype of ionotropic glutamate receptor, containing the subunit NR1 complexed with some combination of the subunits NR2A–NR2D and NR3A or NR3B, that responds selectively to NMDA by gating a cationic channel that is distinguished both by its permeability to Ca2+ and by its voltage-dependent blockade by Mg2+ at the resting membrane potential.
(α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor). The subtype of ionotropic glutamate receptor that contains a tetramer of some combination of the subunits GluR1–GluR4, responds selectively to AMPA by gating a monovalent cation current, and mediates most fast excitatory neurotransmission in the brain.
(Long-term potentiation). A form of synaptic plasticity that is mostly studied in hippocampal CA1 pyramidal neurons but that is found in many other areas of the brain. It is characterized by a persistent enhancement of neurotransmission following an appropriate stimulus (see Hebb's rule).
- Pyramidal neurons
The principal cells of the hippocampus and the neocortex. These large cells use glutamate as their neurotransmitter.
- Paired pulse facilitation
The phenomenon whereby the amplitude of an EPSC that is triggered shortly (for example, 50 ms) after a prior EPSC is increased relative to that of the prior EPSC, reflecting an increased probability of presynaptic vesicle release and probably resulting from an increased presynaptic Ca2+ concentration.
Delivering low-frequency presynaptic stimulation and simultaneously depolarizing the postsynaptic cell. This triggers LTP in a manner that is consistent with Hebb's rule.
- Hebb's rule
(or Hebb's postulate). The notion that after a presynaptic neuron and a postsynaptic neuron fire in unison, the efficiency of neurotransmission between them improves.
An NMDAR antagonist that is use-dependent (that is, it binds inside the open channel pore only after agonist binding) and poorly reversible (that is, once it is in the pore it binds tightly with a very slow unbinding rate).
- Tetanic stimulation
The delivery of a rapid train of presynaptic stimuli through an extracellular stimulating electrode positioned near a bundle of axons, typically to trigger synaptic plasticity.
- Glutamate transporters
Transmembrane proteins that bind extracellular glutamate and transport it into astrocytes and neurons, thereby contributing to the cessation of excitatory synaptic transmission after presynaptic glutamate release.
A drug that binds AMPARs, blocking the normal fast desensitization of these receptors to glutamate.
An ampiphilic styryl dye that reversibly partitions into lipid bilayers; after exposing neurons to this dye, inducing neuronal activity and then washing off the dye, recycled presynaptic vesicles retain a fluorescent signal, which allows visualization of presynaptic boutons under light microscopy.
Ejection of a charged chemical from a high-resistance glass microelectrode through the delivery of a current pulse.
A synapse formed by a neuron onto itself, usually in the context of isolated single-neuron microisland cultures.
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Cite this article
Kerchner, G., Nicoll, R. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci 9, 813–825 (2008). https://doi.org/10.1038/nrn2501
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