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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2003 Apr 29;358(1432):727–733. doi: 10.1098/rstb.2002.1229

Silent synapses: what are they telling us about long-term potentiation?

Dimitri M Kullmann 1
PMCID: PMC1693148  PMID: 12740119

Abstract

At several cortical synapses glutamate release events can be mediated exclusively by NMDA receptors, with no detectable contribution from AMPA receptors. This observation was originally made by comparing the trial-to-trial variability of the two components of synaptic signals evoked in hippocampal neurons, and was subsequently confirmed by recording apparently pure NMDA receptor-mediated EPSCs with stimulation of small numbers of axons. It has come to be known as the 'silent synapse' phenomenon, and is widely assumed to be caused by the absence of functional AMPA receptors, which can, however, be recruited into the postsynaptic density by long-term potentiation (LTP) induction. Thus, it provides an important impetus for relating AMPA receptor trafficking mechanisms to the expression of LTP, a theme that is taken up elsewhere in this issue. This article draws attention to several findings that call for caution in identifying silent synapses exclusively with synapses without AMPA receptors. In addition, it attempts to identify several missing pieces of evidence that are required to show that unsilencing of such synapses is entirely accounted for by insertion of AMPA receptors into the postsynaptic density. Some aspects of the early stages of LTP expression remain open to alternative explanations.

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Selected References

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  1. Asztely F., Erdemli G., Kullmann D. M. Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron. 1997 Feb;18(2):281–293. doi: 10.1016/s0896-6273(00)80268-8. [DOI] [PubMed] [Google Scholar]
  2. Asztely Fredrik, Wigström Holger, Gustafsson Bengt. The Relative Contribution of NMDA Receptor Channels in the Expression of Long-term Potentiation in the Hippocampal CA1 Region. Eur J Neurosci. 1992;4(8):681–690. doi: 10.1111/j.1460-9568.1992.tb00177.x. [DOI] [PubMed] [Google Scholar]
  3. Barbour B. An evaluation of synapse independence. J Neurosci. 2001 Oct 15;21(20):7969–7984. doi: 10.1523/JNEUROSCI.21-20-07969.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bashir Z. I., Alford S., Davies S. N., Randall A. D., Collingridge G. L. Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus. Nature. 1991 Jan 10;349(6305):156–158. doi: 10.1038/349156a0. [DOI] [PubMed] [Google Scholar]
  5. Bekkers J. M., Stevens C. F. Presynaptic mechanism for long-term potentiation in the hippocampus. Nature. 1990 Aug 23;346(6286):724–729. doi: 10.1038/346724a0. [DOI] [PubMed] [Google Scholar]
  6. Bergles D. E., Diamond J. S., Jahr C. E. Clearance of glutamate inside the synapse and beyond. Curr Opin Neurobiol. 1999 Jun;9(3):293–298. doi: 10.1016/s0959-4388(99)80043-9. [DOI] [PubMed] [Google Scholar]
  7. Charton J. P., Herkert M., Becker C. M., Schröder H. Cellular and subcellular localization of the 2B-subunit of the NMDA receptor in the adult rat telencephalon. Brain Res. 1999 Jan 23;816(2):609–617. doi: 10.1016/s0006-8993(98)01243-8. [DOI] [PubMed] [Google Scholar]
  8. Choi S., Klingauf J., Tsien R. W. Postfusional regulation of cleft glutamate concentration during LTP at 'silent synapses'. Nat Neurosci. 2000 Apr;3(4):330–336. doi: 10.1038/73895. [DOI] [PubMed] [Google Scholar]
  9. Cossart R., Tyzio R., Dinocourt C., Esclapez M., Hirsch J. C., Ben-Ari Y., Bernard C. Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons. Neuron. 2001 Feb;29(2):497–508. doi: 10.1016/s0896-6273(01)00221-5. [DOI] [PubMed] [Google Scholar]
  10. Danbolt N. C. Glutamate uptake. Prog Neurobiol. 2001 Sep;65(1):1–105. doi: 10.1016/s0301-0082(00)00067-8. [DOI] [PubMed] [Google Scholar]
  11. Diamond J. S., Bergles D. E., Jahr C. E. Glutamate release monitored with astrocyte transporter currents during LTP. Neuron. 1998 Aug;21(2):425–433. doi: 10.1016/s0896-6273(00)80551-6. [DOI] [PubMed] [Google Scholar]
  12. Durand G. M., Kovalchuk Y., Konnerth A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature. 1996 May 2;381(6577):71–75. doi: 10.1038/381071a0. [DOI] [PubMed] [Google Scholar]
  13. Engert F., Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature. 1999 May 6;399(6731):66–70. doi: 10.1038/19978. [DOI] [PubMed] [Google Scholar]
  14. Gustafsson B., Wigström H. Long-term potentiation in the hippocampal CA1 region: its induction and early temporal development. Prog Brain Res. 1990;83:223–232. doi: 10.1016/s0079-6123(08)61252-2. [DOI] [PubMed] [Google Scholar]
  15. Harris K. M., Sultan P. Variation in the number, location and size of synaptic vesicles provides an anatomical basis for the nonuniform probability of release at hippocampal CA1 synapses. Neuropharmacology. 1995 Nov;34(11):1387–1395. doi: 10.1016/0028-3908(95)00142-s. [DOI] [PubMed] [Google Scholar]
  16. Hosokawa T., Rusakov D. A., Bliss T. V., Fine A. Repeated confocal imaging of individual dendritic spines in the living hippocampal slice: evidence for changes in length and orientation associated with chemically induced LTP. J Neurosci. 1995 Aug;15(8):5560–5573. doi: 10.1523/JNEUROSCI.15-08-05560.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Isaac J. T., Nicoll R. A., Malenka R. C. Evidence for silent synapses: implications for the expression of LTP. Neuron. 1995 Aug;15(2):427–434. doi: 10.1016/0896-6273(95)90046-2. [DOI] [PubMed] [Google Scholar]
  18. Jiang L., Xu J., Nedergaard M., Kang J. A kainate receptor increases the efficacy of GABAergic synapses. Neuron. 2001 May;30(2):503–513. doi: 10.1016/s0896-6273(01)00298-7. [DOI] [PubMed] [Google Scholar]
  19. Jonas P., Major G., Sakmann B. Quantal components of unitary EPSCs at the mossy fibre synapse on CA3 pyramidal cells of rat hippocampus. J Physiol. 1993 Dec;472:615–663. doi: 10.1113/jphysiol.1993.sp019965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kauer J. A., Malenka R. C., Nicoll R. A. A persistent postsynaptic modification mediates long-term potentiation in the hippocampus. Neuron. 1988 Dec;1(10):911–917. doi: 10.1016/0896-6273(88)90148-1. [DOI] [PubMed] [Google Scholar]
  21. Kullmann D. M. Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: implications for long-term potentiation. Neuron. 1994 May;12(5):1111–1120. doi: 10.1016/0896-6273(94)90318-2. [DOI] [PubMed] [Google Scholar]
  22. Kullmann D. M., Asztely F. Extrasynaptic glutamate spillover in the hippocampus: evidence and implications. Trends Neurosci. 1998 Jan;21(1):8–14. doi: 10.1016/s0166-2236(97)01150-8. [DOI] [PubMed] [Google Scholar]
  23. 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. 1996 Sep;17(3):461–474. doi: 10.1016/s0896-6273(00)80178-6. [DOI] [PubMed] [Google Scholar]
  24. Kullmann D. M. Excitatory synapses. Neither too loud nor too quiet. Nature. 1999 May 13;399(6732):111–112. doi: 10.1038/20089. [DOI] [PubMed] [Google Scholar]
  25. Kullmann D. M., Nicoll R. A. Long-term potentiation is associated with increases in quantal content and quantal amplitude. Nature. 1992 May 21;357(6375):240–244. doi: 10.1038/357240a0. [DOI] [PubMed] [Google Scholar]
  26. Kullmann D. M., Siegelbaum S. A. The site of expression of NMDA receptor-dependent LTP: new fuel for an old fire. Neuron. 1995 Nov;15(5):997–1002. doi: 10.1016/0896-6273(95)90089-6. [DOI] [PubMed] [Google Scholar]
  27. Larkman A., Hannay T., Stratford K., Jack J. Presynaptic release probability influences the locus of long-term potentiation. Nature. 1992 Nov 5;360(6399):70–73. doi: 10.1038/360070a0. [DOI] [PubMed] [Google Scholar]
  28. Lehre K. P., Danbolt N. C. The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci. 1998 Nov 1;18(21):8751–8757. doi: 10.1523/JNEUROSCI.18-21-08751.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lester R. A., Clements J. D., Westbrook G. L., Jahr C. E. Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature. 1990 Aug 9;346(6284):565–567. doi: 10.1038/346565a0. [DOI] [PubMed] [Google Scholar]
  30. Liao D., Hessler N. A., Malinow R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature. 1995 Jun 1;375(6530):400–404. doi: 10.1038/375400a0. [DOI] [PubMed] [Google Scholar]
  31. Liao D., Jones A., Malinow R. Direct measurement of quantal changes underlying long-term potentiation in CA1 hippocampus. Neuron. 1992 Dec;9(6):1089–1097. doi: 10.1016/0896-6273(92)90068-o. [DOI] [PubMed] [Google Scholar]
  32. Lüscher C., Malenka R. C., Nicoll R. A. Monitoring glutamate release during LTP with glial transporter currents. Neuron. 1998 Aug;21(2):435–441. doi: 10.1016/s0896-6273(00)80552-8. [DOI] [PubMed] [Google Scholar]
  33. Malenka R. C., Nicoll R. A. Long-term potentiation--a decade of progress? Science. 1999 Sep 17;285(5435):1870–1874. doi: 10.1126/science.285.5435.1870. [DOI] [PubMed] [Google Scholar]
  34. Malinow R., Tsien R. W. Presynaptic enhancement shown by whole-cell recordings of long-term potentiation in hippocampal slices. Nature. 1990 Jul 12;346(6280):177–180. doi: 10.1038/346177a0. [DOI] [PubMed] [Google Scholar]
  35. Malinow Roberto, Malenka Robert C. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002 Mar 4;25:103–126. doi: 10.1146/annurev.neuro.25.112701.142758. [DOI] [PubMed] [Google Scholar]
  36. McAllister A. K., Stevens C. F. Nonsaturation of AMPA and NMDA receptors at hippocampal synapses. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6173–6178. doi: 10.1073/pnas.100126497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Montgomery J. M., Pavlidis P., Madison D. V. Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation. Neuron. 2001 Mar;29(3):691–701. doi: 10.1016/s0896-6273(01)00244-6. [DOI] [PubMed] [Google Scholar]
  38. Muller D., Lynch G. Long-term potentiation differentially affects two components of synaptic responses in hippocampus. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9346–9350. doi: 10.1073/pnas.85.23.9346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Murthy V. N., Stevens C. F. Synaptic vesicles retain their identity through the endocytic cycle. Nature. 1998 Apr 2;392(6675):497–501. doi: 10.1038/33152. [DOI] [PubMed] [Google Scholar]
  40. Nusser Z., Lujan R., Laube G., Roberts J. D., Molnar E., Somogyi P. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron. 1998 Sep;21(3):545–559. doi: 10.1016/s0896-6273(00)80565-6. [DOI] [PubMed] [Google Scholar]
  41. 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. 1990 Jul;10(7):2385–2399. doi: 10.1523/JNEUROSCI.10-07-02385.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Perkel D. J., Nicoll R. A. Evidence for all-or-none regulation of neurotransmitter release: implications for long-term potentiation. J Physiol. 1993 Nov;471:481–500. doi: 10.1113/jphysiol.1993.sp019911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Petersen C. C., Malenka R. C., Nicoll R. A., Hopfield J. J. All-or-none potentiation at CA3-CA1 synapses. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4732–4737. doi: 10.1073/pnas.95.8.4732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Racca C., Stephenson F. A., Streit P., Roberts J. D., Somogyi P. NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J Neurosci. 2000 Apr 1;20(7):2512–2522. doi: 10.1523/JNEUROSCI.20-07-02512.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Renger J. J., Egles C., Liu G. A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation. Neuron. 2001 Feb;29(2):469–484. doi: 10.1016/s0896-6273(01)00219-7. [DOI] [PubMed] [Google Scholar]
  46. Rusakov D. A., Kullmann D. M. Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation. J Neurosci. 1998 May 1;18(9):3158–3170. doi: 10.1523/JNEUROSCI.18-09-03158.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Schikorski T., Stevens C. F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci. 1997 Aug 1;17(15):5858–5867. doi: 10.1523/JNEUROSCI.17-15-05858.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. 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. 1995 Aug;15(2):417–426. doi: 10.1016/0896-6273(95)90045-4. [DOI] [PubMed] [Google Scholar]
  49. Semyanov A., Kullmann D. M. Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat Neurosci. 2001 Jul;4(7):718–723. doi: 10.1038/89506. [DOI] [PubMed] [Google Scholar]
  50. Semyanov A., Kullmann D. M. Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron. 2000 Mar;25(3):663–672. doi: 10.1016/s0896-6273(00)81068-5. [DOI] [PubMed] [Google Scholar]
  51. Shi S. H., Hayashi Y., Petralia R. S., Zaman S. H., Wenthold R. J., Svoboda K., Malinow R. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science. 1999 Jun 11;284(5421):1811–1816. doi: 10.1126/science.284.5421.1811. [DOI] [PubMed] [Google Scholar]
  52. Shigemoto R., Kinoshita A., Wada E., Nomura S., Ohishi H., Takada M., Flor P. J., Neki A., Abe T., Nakanishi S. Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci. 1997 Oct 1;17(19):7503–7522. doi: 10.1523/JNEUROSCI.17-19-07503.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Shigemoto R., Kulik A., Roberts J. D., Ohishi H., Nusser Z., Kaneko T., Somogyi P. Target-cell-specific concentration of a metabotropic glutamate receptor in the presynaptic active zone. Nature. 1996 Jun 6;381(6582):523–525. doi: 10.1038/381523a0. [DOI] [PubMed] [Google Scholar]
  54. Sorra K. E., Harris K. M. Occurrence and three-dimensional structure of multiple synapses between individual radiatum axons and their target pyramidal cells in hippocampal area CA1. J Neurosci. 1993 Sep;13(9):3736–3748. doi: 10.1523/JNEUROSCI.13-09-03736.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Spacek J., Harris K. M. Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J Neurosci. 1997 Jan 1;17(1):190–203. doi: 10.1523/JNEUROSCI.17-01-00190.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Spacek J. Three-dimensional analysis of dendritic spines. III. Glial sheath. Anat Embryol (Berl) 1985;171(2):245–252. doi: 10.1007/BF00341419. [DOI] [PubMed] [Google Scholar]
  57. Takumi Y., Ramírez-León V., Laake P., Rinvik E., Ottersen O. P. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci. 1999 Jul;2(7):618–624. doi: 10.1038/10172. [DOI] [PubMed] [Google Scholar]
  58. 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. 1999 Nov 25;402(6760):421–425. doi: 10.1038/46574. [DOI] [PubMed] [Google Scholar]
  59. Tsien R. W., Malinow R. Long-term potentiation: presynaptic enhancement following postsynaptic activation of Ca(++)-dependent protein kinases. Cold Spring Harb Symp Quant Biol. 1990;55:147–159. doi: 10.1101/sqb.1990.055.01.018. [DOI] [PubMed] [Google Scholar]
  60. Ventura R., Harris K. M. Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci. 1999 Aug 15;19(16):6897–6906. doi: 10.1523/JNEUROSCI.19-16-06897.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Voronin L. L. Quantal analysis of hippocampal long-term potentiation. Rev Neurosci. 1994 Apr-Jun;5(2):141–170. doi: 10.1515/revneuro.1994.5.2.141. [DOI] [PubMed] [Google Scholar]
  62. Yokoi M., Kobayashi K., Manabe T., Takahashi T., Sakaguchi I., Katsuura G., Shigemoto R., Ohishi H., Nomura S., Nakamura K. Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2. Science. 1996 Aug 2;273(5275):645–647. doi: 10.1126/science.273.5275.645. [DOI] [PubMed] [Google Scholar]
  63. Zakharenko S. S., Zablow L., Siegelbaum S. A. Visualization of changes in presynaptic function during long-term synaptic plasticity. Nat Neurosci. 2001 Jul;4(7):711–717. doi: 10.1038/89498. [DOI] [PubMed] [Google Scholar]

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