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AMPA-silent synapses in brain development and pathology

Nature Reviews Neuroscience volume 14, pages 839–850 (2013)Cite this article

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Key Points

  • Glutamatergic synapses are generated without functional AMPA receptor-mediated transmission. These AMPA-silent synapses can become unsilenced either by inactivity or by correlated activity.

  • AMPA unsilencing by correlated activity is the major mechanism underlying long-term potentiation in the developing nervous system.

  • AMPA-silent synapses are largely restricted to the developmental period and disappear by either elimination or stabilization. They do, however, remain on GABAergic neurons in the mature nervous system.

  • The presence of AMPA-silent synapses correlates with critical periods of heightened plasticity and synaptic reorganization.

  • Aberrant selection of AMPA-silent synapses may contribute to neurodevelopmental disorders.

  • De novo generation of AMPA-silent synapses in the mature nervous system may be involved in addiction and synaptic regeneration.

Abstract

Synapses are constantly generated at a high rate in the developing, prepubescent brain. Newly generated glutamatergic synapses lack functional AMPA receptor-mediated transmission. Most of these 'AMPA-silent' synapses are eliminated during the developmental period, but some are specifically selected for AMPA unsilencing by correlated pre-and postsynaptic activity as the first step in a process that leads to stabilization of the synapse. Premature, or delayed, unsilencing of AMPA-silent synapses has been implicated in neurodevelopmental disorders, and abnormal generation of AMPA-silent synapses is associated with brain trauma, addiction and neurodegenerative disorders, further highlighting the importance of AMPA-silent synapses in brain pathology.

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Figure 1: The AMPA-silent synapse — silencing and unsilencing.
Figure 2: AMPA-silent synapses are either stabilized or eliminated.
Figure 3: Activity-dependent selection of AMPA-silent synapses.
Figure 4: Induction of AMPA-silent synapses in brain pathology.

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References

  1. Atwood, H. L. & Wojtowicz, J. M. Silent synapses in neural plasticity: current evidence. Learn. Mem. 6, 542–571 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Dean, P., Porrill, J., Ekerot, C. F. & Jorntell, H. The cerebellar microcircuit as an adaptive filter: experimental and computational evidence. Nature Rev. Neurosci. 11, 30–43 (2010).

    Article  CAS  Google Scholar 

  3. Megias, M., Emri, Z., Freund, T. F. & Gulyas, A. I. Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells. Neuroscience 102, 527–540 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Lisman, J. & Raghavachari, S. A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Sci. STKE 2006, re11 (2006).

    Article  PubMed  Google Scholar 

  5. Loebel, A., Le Bé, J. V., Richardson, M. J., Markram, H. & Herz, A. V. Matched pre- and post-synaptic changes underlie synaptic plasticity over long time scales. J. Neurosci. 33, 6257–6266 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kerchner, G. A. & Nicoll, R. A. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nature Rev. Neurosci. 9, 813–825 (2008).

    Article  CAS  Google Scholar 

  7. Durand, G. M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Isaac, J. T., Nicoll, R. A. & Malenka, R. C. Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427–434 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. 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 study provides one of the first demonstrations, together with references 7 and 8, of AMPA-silent synapses.

    Article  CAS  PubMed  Google Scholar 

  10. Kullmann, D. M. Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: implications for long-term potentiation. Neuron 12, 1111–1120 (1994). This study shows that the cv for AMPA EPSCs is larger than for NMDA EPSCs in the same synapse population and that this difference decreases after LTP. This result suggests recruitment of 'latent' AMPA clusters as one possible explanation for LTP.

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Minichiello, L. TrkB signalling pathways in LTP and learning. Nature Rev. Neurosci. 10, 850–860 (2009).

    Article  CAS  Google Scholar 

  14. Itami, C. et al. Brain-derived neurotrophic factor-dependent unmasking of “silent” synapses in the developing mouse barrel cortex. Proc. Natl Acad. Sci. USA 100, 13069–13074 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ward, B. et al. State-dependent mechanisms of LTP expression revealed by optical quantal analysis. Neuron 52, 649–661 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Jurado, S. et al. LTP requires a unique postsynaptic SNARE fusion machinery. Neuron 77, 542–558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lledo, P. M., Zhang, X., Sudhof, T. C., Malenka, R. C. & Nicoll, R. A. Postsynaptic membrane fusion and long-term potentiation. Science 279, 399–403 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Opazo, P., Sainlos, M. & Choquet, D. Regulation of AMPA receptor surface diffusion by PSD-95 slots. Curr. Opin. Neurobiol. 22, 453–460 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Sametsky, E. A., Disterhoft, J. F., Geinisman, Y. & Nicholson, D. A. Synaptic strength and postsynaptically silent synapses through advanced aging in rat hippocampal CA1 pyramidal neurons. Neurobiol. Aging 31, 813–825 (2010).

    Article  PubMed  Google Scholar 

  21. Hsia, A. Y., Malenka, R. C. & Nicoll, R. A. Development of excitatory circuitry in the hippocampus. J. Neurophysiol. 79, 2013–2024 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Riebe, I. & Hanse, E. Development of synaptic connectivity onto interneurons in stratum radiatum in the CA1 region of the rat hippocampus. BMC Neurosci. 13, 14 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. Peled, E. S. & Isacoff, E. Y. Optical quantal analysis of synaptic transmission in wild-type and rab3-mutant Drosophila motor axons. Nature Neurosci. 14, 519–526 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Yasuda, H., Barth, A. L., Stellwagen, D. & Malenka, R. C. A developmental switch in the signaling cascades for LTP induction. Nature Neurosci. 6, 15–16 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Wikstrom, M. A., Matthews, P., Roberts, D., Collingridge, G. L. & Bortolotto, Z. A. Parallel kinase cascades are involved in the induction of LTP at hippocampal CA1 synapses. Neuropharmacology 45, 828–836 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Lu, H. C. et al. Adenylyl cyclase I regulates AMPA receptor trafficking during mouse cortical 'barrel' map development. Nature Neurosci. 6, 939–947 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Jensen, V. et al. A juvenile form of postsynaptic hippocampal long-term potentiation in mice deficient for the AMPA receptor subunit GluR-A. J. Physiol. 553, 843–856 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhu, J. J., Esteban, J. A., Hayashi, Y. & Malinow, R. Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity. Nature Neurosci. 3, 1098–1106 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Kolleker, A. et al. Glutamatergic plasticity by synaptic delivery of GluR-Blong-containing AMPA receptors. Neuron 40, 1199–1212 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Esteban, J. A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nature Neurosci. 6, 136–143 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Cao, G. & Harris, K. M. Developmental regulation of the late phase of long-term potentiation (L-LTP) and metaplasticity in hippocampal area CA1 of the rat. J. Neurophysiol. 107, 902–912 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Bellone, C. & Nicoll, R. A. Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55, 779–785 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Yoshii, A. & Constantine-Paton, M. BDNF induces transport of PSD-95 to dendrites through PI3K–AKT signaling after NMDA receptor activation. Nature Neurosci. 10, 702–711 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Cabezas, C. & Buno, W. BDNF is required for the induction of a presynaptic component of the functional conversion of silent synapses. Hippocampus 21, 374–385 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Lauri, S. E. et al. Functional maturation of CA1 synapses involves activity-dependent loss of tonic kainate receptor-mediated inhibition of glutamate release. Neuron 50, 415–429 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Palmer, M. J., Isaac, J. T. & Collingridge, G. L. Multiple, developmentally regulated expression mechanisms of long-term potentiation at CA1 synapses. J. Neurosci. 24, 4903–4911 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Abrahamsson, T., Gustafsson, B. & Hanse, E. AMPA silencing is a prerequisite for developmental long-term potentiation in the hippocampal CA1 region. J. Neurophysiol. 100, 2605–2614 (2008).

    Article  PubMed  Google Scholar 

  39. Isaac, J. T., Crair, M. C., Nicoll, R. A. & Malenka, R. C. Silent synapses during development of thalamocortical inputs. Neuron 18, 269–280 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Clement, J. P., Ozkan, E. D., Aceti, M., Miller, C. A. & Rumbaugh, G. SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity. J. Neurosci. 33, 10447–10452 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ben-Ari, Y. Excitatory actions of gaba during development: the nature of the nurture. Nature Rev. Neurosci. 3, 728–739 (2002).

    Article  CAS  Google Scholar 

  42. Hanse, E., Durand, G. M., Garaschuk, O. & Konnerth, A. Activity-dependent wiring of the developing hippocampal neuronal circuit. Semin. Cell Dev. Biol. 8, 35–42 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Leinekugel, X., Medina, I., Khalilov, I., Ben-Ari, Y. & Khazipov, R. Ca2+ oscillations mediated by the synergistic excitatory actions of GABAA and NMDA receptors in the neonatal hippocampus. Neuron 18, 243–255 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Blankenship, A. G. & Feller, M. B. Mechanisms underlying spontaneous patterned activity in developing neural circuits. Nature Rev. Neurosci. 11, 18–29 (2010).

    Article  CAS  Google Scholar 

  45. Garaschuk, O., Hanse, E. & Konnerth, A. Developmental profile and synaptic origin of early network oscillations in the CA1 region of rat neonatal hippocampus. J. Physiol. 507, 219–236 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Minlebaev, M., Colonnese, M., Tsintsadze, T., Sirota, A. & Khazipov, R. Early gamma oscillations synchronize developing thalamus and cortex. Science 334, 226–229 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Khazipov, R. & Luhmann, H. J. Early patterns of electrical activity in the developing cerebral cortex of humans and rodents. Trends Neurosci. 29, 414–418 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Chancey, J. H. et al. GABA depolarization is required for experience-dependent synapse unsilencing in adult-born neurons. J. Neurosci. 33, 6614–6622 (2013). This study provides the first direct evidence that depolarizing GABA activity is necessary for AMPA unsilencing in immature neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Huupponen, J., Molchanova, S. M., Lauri, S. E. & Taira, T. Ongoing intrinsic synchronous activity is required for the functional maturation of CA3–CA1 glutamatergic synapses. Cereb. Cortex 23, 2754–2764 (2013).

    Article  PubMed  Google Scholar 

  51. Ashby, M. C. & Isaac, J. T. Maturation of a recurrent excitatory neocortical circuit by experience-dependent unsilencing of newly formed dendritic spines. Neuron 70, 510–521 (2011). This work shows that sensory inputs cause unsilencing of AMPA-silent synapses in the barrel cortex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

  53. Strandberg, J., Wasling, P. & Gustafsson, B. Modulation of low-frequency-induced synaptic depression in the developing CA3–CA1 hippocampal synapses by NMDA and metabotropic glutamate receptor activation. J. Neurophysiol. 101, 2252–2262 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Wasling, P., Strandberg, J. & Hanse, E. AMPA receptor activation causes silencing of AMPA receptor-mediated synaptic transmission in the developing hippocampus. PLoS ONE 7, e34474 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Groc, L., Gustafsson, B. & Hanse, E. Spontaneous unitary synaptic activity in CA1 pyramidal neurons during early postnatal development: constant contribution of AMPA and NMDA receptors. J. Neurosci. 22, 5552–5562 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Friedman, H. V., Bresler, T., Garner, C. C. & Ziv, N. E. Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment. Neuron 27, 57–69 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Hall, B. J. & Ghosh, A. Regulation of AMPA receptor recruitment at developing synapses. Trends Neurosci. 31, 82–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Xiao, M. Y., Wasling, P., Hanse, E. & Gustafsson, B. Creation of AMPA-silent synapses in the neonatal hippocampus. Nature Neurosci. 7, 236–243 (2004). The first demonstration of AMPA silencing; the authors show that AMPA-silent synapses are kept silent by sparse activity.

    Article  CAS  PubMed  Google Scholar 

  59. Zito, K., Scheuss, V., Knott, G., Hill, T. & Svoboda, K. Rapid functional maturation of nascent dendritic spines. Neuron 61, 247–258 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Heine, M. et al. Activity-independent and subunit-specific recruitment of functional AMPA receptors at neurexin/neuroligin contacts. Proc. Natl Acad. Sci. USA 105, 20947–20952 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Groc, L., Gustafsson, B. & Hanse, E. AMPA signalling in nascent glutamatergic synapses: there and not there! Trends Neurosci. 29, 132–139 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Nair, D. et al. Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J. Neurosci. 33, 13204–13224 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Meng, K., Li, Y. H., Zhang, L., Li, P. & Han, T. Z. Ca2+-permeable AMPA receptors mediate induction of test pulse depression of naive synapses in rat visual cortical slices at early postnatal stage. Neuroscience 165, 684–691 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Strandberg, J. & Gustafsson, B. Critical and complex role of N-methyl-d-aspartate receptors in long-term depression at CA3–CA1 synapses in the developing hippocampus. Neuroscience 192, 54–66 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Abrahamsson, T., Gustafsson, B. & Hanse, E. Synaptic fatigue at the naive perforant path-dentate granule cell synapse in the rat. J. Physiol. 569, 737–750 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Riebe, I., Gustafsson, B. & Hanse, E. Silent synapses onto interneurons in the rat CA1 stratum radiatum. Eur. J. Neurosci. 29, 1870–1882 (2009).

    Article  PubMed  Google Scholar 

  67. Nabavi, S. et al. Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression. Proc. Natl Acad. Sci. USA 110, 4027–4032 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liao, D. & Malinow, R. Deficiency in induction but not expression of LTP in hippocampal slices from young rats. Learn. Mem. 3, 138–149 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Destexhe, A., Rudolph, M. & Pare, D. The high-conductance state of neocortical neurons in vivo. Nature Rev. Neurosci. 4, 739–751 (2003).

    Article  CAS  Google Scholar 

  70. Luthi, A. et al. Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF–GluR2 interaction. Neuron 24, 389–399 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Sanderson, T. M., Collingridge, G. L. & Fitzjohn, S. M. Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs. Mol. Brain 4, 30 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wan, Y., Feng, G. & Calakos, N. Sapap3 deletion causes mGluR5-dependent silencing of AMPAR synapses. J. Neurosci. 31, 16685–16691 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Scholz, R. et al. AMPA receptor signaling through BRAG2 and Arf6 critical for long-term synaptic depression. Neuron 66, 768–780 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Petralia, R. S., Sans, N., Wang, Y. X. & Wenthold, R. J. Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol. Cell Neurosci. 29, 436–452 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Montgomery, J. M. & Madison, D. V. Discrete synaptic states define a major mechanism of synapse plasticity. Trends Neurosci. 27, 744–750 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Hill, T. C. & Zito, K. LTP-induced long-term stabilization of individual nascent dendritic spines. J. Neurosci. 33, 678–686 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ripley, B., Otto, S., Tiglio, K., Williams, M. E. & Ghosh, A. Regulation of synaptic stability by AMPA receptor reverse signaling. Proc. Natl Acad. Sci. USA 108, 367–372 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Tracy, T. E., Yan, J. J. & Chen, L. Acute knockdown of AMPA receptors reveals a trans-synaptic signal for presynaptic maturation. EMBO J. 30, 1577–1592 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lu, W. et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62, 254–268 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sanz-Clemente, A., Nicoll, R. A. & Roche, K. W. Diversity in NMDA receptor composition: many regulators, many consequences. Neuroscientist 19, 62–75 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Tovar, K. R., McGinley, M. J. & Westbrook, G. L. Triheteromeric NMDA receptors at hippocampal synapses. J. Neurosci. 33, 9150–9160 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Groc, L. et al. NMDA receptor surface mobility depends on NR2A-2B subunits. Proc. Natl Acad. Sci. USA 103, 18769–18774 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lavezzari, G., McCallum, J., Dewey, C. M. & Roche, K. W. Subunit-specific regulation of NMDA receptor endocytosis. J. Neurosci. 24, 6383–6391 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Groc, L., Bard, L. & Choquet, D. Surface trafficking of N-methyl-d-aspartate receptors: physiological and pathological perspectives. Neuroscience 158, 4–18 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Zhu, J. J. & Malinow, R. Acute versus chronic NMDA receptor blockade and synaptic AMPA receptor delivery. Nature Neurosci. 5, 513–514 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. 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). The authors of this study present the surprising finding that chronic inhibition of NMDARs results in fewer AMPA-silent synapses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hall, B. J., Ripley, B. & Ghosh, A. NR2B signaling regulates the development of synaptic AMPA receptor current. J. Neurosci. 27, 13446–13456 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Colonnese, M. T., Shi, J. & Constantine-Paton, M. Chronic NMDA receptor blockade from birth delays the maturation of NMDA currents, but does not affect AMPA/kainate currents. J. Neurophysiol. 89, 57–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Gray, J. A. et al. Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron 71, 1085–1101 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Henson, M. A. et al. Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS ONE 7, e42327 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Roberts, A. C. et al. Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63, 342–356 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lu, W., Bushong, E. A., Shih, T. P., Ellisman, M. H. & Nicoll, R. A. The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function. Neuron 78, 433–439 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zheng, C. Y., Seabold, G. K., Horak, M. & Petralia, R. S. MAGUKs, synaptic development, and synaptic plasticity. Neuroscientist 17, 493–512 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zheng, C. Y., Petralia, R. S., Wang, Y. X., Kachar, B. & Wenthold, R. J. SAP102 is a highly mobile MAGUK in spines. J. Neurosci. 30, 4757–4766 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen, B. S. et al. SAP102 mediates synaptic clearance of NMDA receptors. Cell Rep. 2, 1120–1128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zheng, S. et al. PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2. Nature Neurosci. 15, 381–388 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Ehrlich, I., Klein, M., Rumpel, S. & Malinow, R. PSD-95 is required for activity-driven synapse stabilization. Proc. Natl Acad. Sci. USA 104, 4176–4181 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. El-Husseini, A. E., Schnell, E., Chetkovich, D. M., Nicoll, R. A. & Bredt, D. S. PSD-95 involvement in maturation of excitatory synapses. Science 290, 1364–1368 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. De Roo, M., Klauser, P., Mendez, P., Poglia, L. & Muller, D. Activity-dependent PSD formation and stabilization of newly formed spines in hippocampal slice cultures. Cereb. Cortex 18, 151–161 (2008).

    Article  PubMed  Google Scholar 

  100. Elias, G. M., Elias, L. A., Apostolides, P. F., Kriegstein, A. R. & Nicoll, R. A. Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development. Proc. Natl Acad. Sci. USA 105, 20953–20958 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Beique, J. C. et al. Synapse-specific regulation of AMPA receptor function by PSD-95. Proc. Natl Acad. Sci. USA 103, 19535–19540 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Collingridge, G. L., Peineau, S., Howland, J. G. & Wang, Y. T. Long-term depression in the CNS. Nature Rev. Neurosci. 11, 459–473 (2010).

    Article  CAS  Google Scholar 

  103. Hanse, E., Taira, T., Lauri, S. & Groc, L. Glutamate synapse in developing brain: an integrative perspective beyond the silent state. Trends Neurosci. 32, 532–537 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Morishita, W., Marie, H. & Malenka, R. C. Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses. Nature Neurosci. 8, 1043–1050 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Xiao, M. Y., Karpefors, M., Niu, Y. P. & Wigstrom, H. The complementary nature of long-term depression and potentiation revealed by dual component excitatory postsynaptic potentials in hippocampal slices from young rats. Neuroscience 68, 625–635 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Xiao, M. Y., Wigstrom, H. & Gustafsson, B. Long-term depression in the hippocampal CA1 region is associated with equal changes in AMPA and NMDA receptor-mediated synaptic potentials. Eur. J. Neurosci. 6, 1055–1057 (1994).

    Article  CAS  PubMed  Google Scholar 

  107. Montgomery, J. M. & Madison, D. V. State-dependent heterogeneity in synaptic depression between pyramidal cell pairs. Neuron 33, 765–777 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. O'Connor, D. H., Wittenberg, G. M. & Wang, S. S. Graded bidirectional synaptic plasticity is composed of switch-like unitary events. Proc. Natl Acad. Sci. USA 102, 9679–9684 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Becker, N., Wierenga, C. J., Fonseca, R., Bonhoeffer, T. & Nagerl, U. V. LTD induction causes morphological changes of presynaptic boutons and reduces their contacts with spines. Neuron 60, 590–597 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Bastrikova, N., Gardner, G. A., Reece, J. M., Jeromin, A. & Dudek, S. M. Synapse elimination accompanies functional plasticity in hippocampal neurons. Proc. Natl Acad. Sci. USA 105, 3123–3127 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Shinoda, Y., Tanaka, T., Tominaga-Yoshino, K. & Ogura, A. Persistent synapse loss induced by repetitive LTD in developing rat hippocampal neurons. PLoS ONE 5, e10390 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Oh, W. C., Hill, T. C. & Zito, K. Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening. Proc. Natl Acad. Sci. USA 110, E305–E312 (2013).

    CAS  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. Colonnese, M. T., Zhao, J.-P. & Constantine-Paton, M. NMDA receptor currents suppress synapse formation on sprouting axons in vivo. J. Neurosci. 25, 1291–1303 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Colonnese, M. T. & Constantine-Paton, M. Developmental period for N-methyl-D-aspartate (NMDA) receptor-dependent synapse elimination correlated with visuotopic map refinement. J. Comp. Neurol. 494, 738–751 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wasling, P. et al. Synaptic retrogenesis and amyloid-beta in Alzheimer's disease. J. Alzheimers Dis. 16, 1–14 (2009).

    Article  CAS  PubMed  Google Scholar 

  117. Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006). This study shows that amyloid-β causes removal of synaptic AMPARs through LTD-like mechanisms and that this removal of AMPARs is necessary for subsequent spine elimination.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kamenetz, F. et al. APP processing and synaptic function. Neuron 37, 925–937 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Ting, J. T., Kelley, B. G., Lambert, T. J., Cook, D. G. & Sullivan, J. M. Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms. Proc. Natl Acad. Sci. USA 104, 353–358 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Kessels, H. W., Nabavi, S. & Malinow, R. Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression. Proc. Natl Acad. Sci. USA 110, 4033–4038 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Flavell, S. W. et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Tsai, N. P. et al. Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 151, 1581–1594 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Clarke, L. E. & Barres, B. A. Emerging roles of astrocytes in neural circuit development. Nature Rev. Neurosci. 14, 311–321 (2013).

    Article  CAS  Google Scholar 

  124. Kettenmann, H., Kirchhoff, F. & Verkhratsky, A. Microglia: new roles for the synaptic stripper. Neuron 77, 10–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. O'Brien, R. J. et al. Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp. Neuron 23, 309–323 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Sia, G. M. et al. Interaction of the N-terminal domain of the AMPA receptor GluR4 subunit with the neuronal pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron 55, 87–102 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Geiger, J. R. et al. Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 15, 193–204 (1995).

    Article  CAS  PubMed  Google Scholar 

  128. Perry, V. H. & O'Connor, V. C1q: the perfect complement for a synaptic feast? Nature Rev. Neurosci. 9, 807–811 (2008).

    Article  CAS  Google Scholar 

  129. Koch, S. M. & Ullian, E. M. Neuronal pentraxins mediate silent synapse conversion in the developing visual system. J. Neurosci. 30, 5404–5414 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hensch, T. K. Critical period plasticity in local cortical circuits. Nature Rev. Neurosci. 6, 877–888 (2005).

    Article  CAS  Google Scholar 

  131. Wang, D. & Fawcett, J. The perineuronal net and the control of CNS plasticity. Cell Tissue Res. 349, 147–160 (2012).

    Article  PubMed  Google Scholar 

  132. Funahashi, R., Maruyama, T., Yoshimura, Y. & Komatsu, Y. Silent synapses persist into adulthood in layer 2/3 pyramidal neurons of visual cortex in dark-reared mice. J. Neurophysiol. 109, 2064–2076 (2013).

    Article  PubMed  Google Scholar 

  133. Woolley, C. S., Weiland, N. G., McEwen, B. S. & Schwartzkroin, P. A. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density. J. Neurosci. 17, 1848–1859 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Smith, C. C. & McMahon, L. L. Estrogen-induced increase in the magnitude of long-term potentiation occurs only when the ratio of NMDA transmission to AMPA transmission is increased. J. Neurosci. 25, 7780–7791 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Srivastava, D. P. et al. Rapid enhancement of two-step wiring plasticity by estrogen and NMDA receptor activity. Proc. Natl Acad. Sci. USA 105, 14650–14655 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Isope, P. & Barbour, B. Properties of unitary granule cell→ Purkinje cell synapses in adult rat cerebellar slices. J. Neurosci. 22, 9668–9678 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Grueter, B. A., Robison, A. J., Neve, R. L., Nestler, E. J. & Malenka, R. C. FosB differentially modulates nucleus accumbens direct and indirect pathway function. Proc. Natl Acad. Sci. USA 110, 1923–1928 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Huang, Y. H. et al. In vivo cocaine experience generates silent synapses. Neuron 63, 40–47 (2009). The authors of this study present evidence that cocaine exposure can induce de novo generation of AMPA-silent synapses in the mature nervous system.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Brown, T. E. et al. A silent synapse-based mechanism for cocaine-induced locomotor sensitization. J. Neurosci. 31, 8163–8174 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Koya, E. et al. Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization. Nature Neurosci. 15, 1556–1562 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. Penzes, P., Cahill, M. E., Jones, K. A., VanLeeuwen, J.-E. & Woolfrey, K. M. Dendritic spine pathology in neuropsychiatric disorders. Nature Neurosci. 14, 285–293 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Bhakar, A. L., Dolen, G. & Bear, M. F. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Harlow, E. G. et al. Critical period plasticity is disrupted in the barrel cortex of Fmr1 knockout mice. Neuron 65, 385–398 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ran, I. et al. Selective regulation of GluA subunit synthesis and AMPA receptor-mediated synaptic function and plasticity by the translation repressor 4E-BP2 in hippocampal pyramidal cells. J. Neurosci. 33, 1872–1886 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Rumbaugh, G., Adams, J. P., Kim, J. H. & Huganir, R. L. SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc. Natl Acad. Sci. USA 103, 4344–4351 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Clement, J. P. et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151, 709–723 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Talos, D. M. et al. The interaction between early life epilepsy and autistic-like behavioral consequences: a role for the mammalian target of rapamycin (mTOR) pathway. PLoS ONE 7, e35885 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhou, C., Lippman, J. J., Sun, H. & Jensen, F. E. Hypoxia-induced neonatal seizures diminish silent synapses and long-term potentiation in hippocampal CA1 neurons. J. Neurosci. 31, 18211–18222 (2011). This study shows that there are fewer AMPA-silent synapses and that there is impaired LTP following seizures in the neonatal period. This gives one mechanistic suggestion for how neonatal seizures may lead to cognitive deficits.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Quintana, P., Alberi, S., Hakkoum, D. & Muller, D. Glutamate receptor changes associated with transient anoxia/hypoglycaemia in hippocampal slice cultures. Eur. J. Neurosci. 23, 975–983 (2006).

    Article  PubMed  Google Scholar 

  150. Iwasato, T. et al. Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406, 726–731 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Marie, H., Morishita, W., Yu, X., Calakos, N. & Malenka, R. C. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 45, 741–752 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Lee, B. R. & Dong, Y. Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond. Neuropharmacology 61, 1060–1069 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wall, P. D. The presence of ineffective synapses and the circumstances which unmask them. Phil. Trans. R. Soc. Lond. B 278, 361–372 (1977).

    Article  CAS  Google Scholar 

  154. Wall, P. D. Recruitment of ineffective synapses after injury. Adv. Neurol. 47, 387–400 (1988).

    CAS  PubMed  Google Scholar 

  155. Kerchner, G. A., Li, P. & Zhuo, M. Speaking out of turn: a role for silent synapses in pain. IUBMB Life 48, 251–256 (1999).

    Article  CAS  PubMed  Google Scholar 

  156. Torsney, C. Inflammatory pain unmasks heterosynaptic facilitation in lamina I neurokinin 1 receptor-expressing neurons in rat spinal cord. J. Neurosci. 31, 5158–5168 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Lo, F. S., Zhao, S. & Erzurumlu, R. S. Astrocytes promote peripheral nerve injury-induced reactive synaptogenesis in the neonatal CNS. J. Neurophysiol. 106, 2876–2887 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 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). This study illustrates that a trauma caused by transection of the trigeminal nerve results in a greater number of AMPA-silent synapses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Eroglu, C. et al. Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139, 380–392 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Nakayama, K., Kiyosue, K. & Taguchi, T. Diminished neuronal activity increases neuron–neuron connectivity underlying silent synapse formation and the rapid conversion of silent to functional synapses. J. Neurosci. 25, 4040–4051 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Arendt, K. L., Sarti, F. & Chen, L. Chronic inactivation of a neural circuit enhances LTP by inducing silent synapse formation. J. Neurosci. 33, 2087–2096 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

    Article  CAS  PubMed  Google Scholar 

  164. Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nature Neurosci. 8, 1051–1058 (2005).

    Article  CAS  PubMed  Google Scholar 

  165. Krishnaswamy, A. & Cooper, E. An activity-dependent retrograde signal induces the expression of the high-affinity choline transporter in cholinergic neurons. Neuron 61, 272–286 (2009).

    Article  CAS  PubMed  Google Scholar 

  166. Crawford, D. C. & Mennerick, S. Presynaptically silent synapses: dormancy and awakening of presynaptic vesicle release. Neuroscientist 18, 216–223 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Hanse, E. & Gustafsson, B. Vesicle release probability and pre-primed pool at glutamatergic synapses in area CA1 of the rat neonatal hippocampus. J. Physiol. 531, 481–493 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Sivakumaran, S., Mohajerani, M. H. & Cherubini, E. At immature mossy-fiber–CA3 synapses, correlated presynaptic and postsynaptic activity persistently enhances GABA release and network excitability via BDNF and cAMP-dependent PKA. J. Neurosci. 29, 2637–2647 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Voronin, L. L. & Cherubini, E. “Presynaptic silence” may be golden. Neuropharmacology 45, 439–449 (2003).

    Article  CAS  PubMed  Google Scholar 

  170. Wu, G., Malinow, R. & Cline, H. T. Maturation of a central glutamatergic synapse. Science 274, 972–976 (1996).

    Article  CAS  PubMed  Google Scholar 

  171. Ali, D. W., Buss, R. R. & Drapeau, P. Properties of miniature glutamatergic EPSCs in neurons of the locomotor regions of the developing zebrafish. J. Neurophysiol. 83, 181–191 (2000).

    Article  CAS  PubMed  Google Scholar 

  172. Mokin, M., Zheng, Z. & Keifer, J. Conversion of silent synapses into the active pool by selective GluR1-3 and GluR4 AMPAR trafficking during in vitro classical conditioning. J. Neurophysiol. 98, 1278–1286 (2007).

    Article  CAS  PubMed  Google Scholar 

  173. Bottjer, S. W. Silent synapses in a thalamo-cortical circuit necessary for song learning in zebra finches. J. Neurophysiol. 94, 3698–3707 (2005).

    Article  CAS  PubMed  Google Scholar 

  174. Kim, J.-H. et al. Presynaptic activation of silent synapses and growth of new synapses contribute to intermediate and long-term facilitation in Aplysia. Neuron 40, 151–165 (2003).

    Article  CAS  PubMed  Google Scholar 

  175. Losonczy, A., Biro, A. A. & Nusser, Z. Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. Proc. Natl Acad. Sci. USA 101, 1362–1367 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Rao, A., Cha, E. M. & Craig, A. M. Mismatched appositions of presynaptic and postsynaptic components in isolated hippocampal neurons. J. Neurosci. 20, 8344–8353 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Bekkers, J. M. Presynaptically silent GABA synapses in hippocampus. J. Neurosci. 25, 4031–4039 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Faber, D. S. & Korn, H. Applicability of the coefficient of variation method for analyzing synaptic plasticity. Biophys. J. 60, 1288–1294 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 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).

    Article  CAS  PubMed  Google Scholar 

  180. 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).

    Article  CAS  PubMed  Google Scholar 

  181. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 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).

    Article  CAS  PubMed  Google Scholar 

  183. Nusser, Z. et al. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21, 545–559 (1998).

    Article  CAS  PubMed  Google Scholar 

  184. 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).

    Article  CAS  PubMed  Google Scholar 

  185. Choi, S., Klingauf, J. & Tsien, R. W. Postfusional regulation of cleft glutamate concentration during LTP at 'silent synapses'. Nature Neurosci. 3, 330–336 (2000).

    Article  CAS  PubMed  Google Scholar 

  186. Kullmann, D. M. & Asztely, F. Extrasynaptic glutamate spillover in the hippocampus: evidence and implications. Trends Neurosci. 21, 8–14 (1998).

    Article  CAS  PubMed  Google Scholar 

  187. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Losi, G., Prybylowski, K., Fu, Z., Luo, J. H. & Vicini, S. Silent synapses in developing cerebellar granule neurons. J. Neurophysiol. 87, 1263–1270 (2002).

    Article  CAS  PubMed  Google Scholar 

  190. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank B. Gustafsson, P. Wasling, J. Strandberg and A. Björefeldt for feedback on previous versions of this manuscript. This work was supported by the Swedish Research Council (K2013-62X-12600-16-4), Swedish State Support for Clinical Research (ALFGBG-136991) and The Swedish Brain Foundation (FO2011-003).

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  1. Department of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, PO Box 100, Gothenburg, SE-405 30, Sweden

    Eric Hanse, Henrik Seth & Ilse Riebe

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AMPA silent synapses in different species and CNS regions (PDF 468 kb)

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Glossary

Ionotropic glutamate receptors

Ligand-gated cation channels that have a tetrameric substructure. There are three main types: NMDA receptors, AMPA receptors and kainate receptors.

Postsynaptic density

(PSD). The protein-rich postsynaptic part of a synapse that appears electron-dense in electron microscopy.

Barrel cortex

The part of rodent primary somatosensory cortex that contains 'barrel-shaped' structures, which receive contralateral sensory input from the whiskers.

Calcium chelator

A molecule that binds calcium ions and thus reduces the concentration of free calcium.

Autapses

Synapses that a neuron makes onto itself such that the pre- and postsynapse are from the same neuron.

Principal neurons

Neurons with axons that project out of the brain region in which their somata lie.

Uncaged glutamate

This term refers to an inactivated form of glutamate that becomes activated using a light source — for example, a laser — of a specific wavelength.

Complement system

The complement system is part of the innate immune system and is implicated in the elimination of synapses in the nervous system.

Perineuronal nets

Specialized extracellular matrix that surrounds the somata and proximal dendrites of certain cell types. They are important for synaptic stabilization and have been suggested to be crucial for the closure of critical periods.

Autism spectrum disorders

A group of neurodevelopmental disorders associated with impairments in social interactions and communication, and with restricted, repetitive and stereotyped patterns of behaviour.

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Hanse, E., Seth, H. & Riebe, I. AMPA-silent synapses in brain development and pathology. Nat Rev Neurosci 14, 839–850 (2013). https://doi.org/10.1038/nrn3642

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