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Creation of AMPA-silent synapses in the neonatal hippocampus

Nature Neuroscience volume 7, pages 236–243 (2004)Cite this article

Abstract

In the developing brain, many glutamate synapses have been found to transmit only NMDA receptor–mediated signaling, that is, they are AMPA-silent. This result has been taken to suggest that glutamate synapses are initially AMPA-silent when they are formed, and that AMPA signaling is acquired through activity-dependent synaptic plasticity. The present study on CA3–CA1 synapses in the hippocampus of the neonatal rat suggests that AMPA-silent synapses are created through a form of activity-dependent silencing of AMPA signaling. We found that AMPA signaling, but not NMDA signaling, could be very rapidly silenced by presynaptic electrical stimulation at frequencies commonly used to probe synaptic function (0.05–1 Hz). Although this AMPA silencing required a rise in postsynaptic Ca2+, it did not require activation of NMDA receptors, metabotropic glutamate receptors or voltage-gated calcium channels. The AMPA silencing, possibly explained by a removal of postsynaptic AMPA receptors, could subsequently be reversed by paired presynaptic and postsynaptic activity.

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Figure 1: Test frequency stimulation induces depression at naive neonatal glutamate synapses.
Figure 2: EPSC depression is selective for AMPA receptor–mediated transmission.
Figure 3: Stable NMDA EPSCs in the presence of the low-affinity NMDA receptor antagonist L-AP5.
Figure 4: The AMPA EPSC depression requires a rise in postsynaptic calcium.
Figure 5: Changes in PPR and EPSC variability (1/CV2) associated with AMPA EPSC depression.
Figure 6: AMPA EPSC depression is expressed as silencing of AMPA signaling.
Figure 7: Hebbian induction of AMPA signaling at previously silenced synapses.

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References

  1. 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  Google Scholar 

  2. Diabira, D., Hennou, S., Chevassus-Au-Louis, N., Ben-Ari, Y. & Gozlan, H. Late embryonic expression of AMPA receptor function in the CA1 region of the intact hippocampus in vitro. Eur. J. Neurosci. 11, 4015–4023 (1999).

    Article  CAS  Google Scholar 

  3. Kutsuwada, T. et al. Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice. Neuron 16, 333–344 (1996).

    Article  CAS  Google Scholar 

  4. Varoqueaux, F. et al. Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. Proc. Natl. Acad. Sci. USA 99, 9037–9042 (2002).

    Article  CAS  Google Scholar 

  5. Verhage, M. et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287, 864–869 (2000).

    Article  CAS  Google Scholar 

  6. Groc, L., Gustafsson, B. & Hanse, E. In vivo evidence for an activity-independent maturation of AMPA/NMDA signaling in the developing hippocampus. Neuroscience 121, 65–72 (2003).

    Article  CAS  Google Scholar 

  7. 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  Google Scholar 

  8. 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 Central  Google Scholar 

  9. 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 Central  Google Scholar 

  10. Hanse, E. & Gustafsson, B. Quantal variability at glutamatergic synapses in area CA1 of the rat neonatal hippocampus. J. Physiol. 531, 467–480 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Malenka, R.C. & Nicoll, R.A. Silent synapses speak up. Neuron 19, 473–476 (1997).

    Article  CAS  PubMed Central  Google Scholar 

  16. Cohen-Cory, S. The developing synapse: construction and modulation of synaptic structures and circuits. Science 298, 770–776 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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. Nat. Neurosci. 4, 1102–1107 (2001).

    Article  CAS  Google Scholar 

  19. Bayer, S.A. Development of the hippocampal region in the rat. II. Morphogenesis during embryonic and early postnatal life. J. Comp. Neurol. 190, 115–134 (1980).

    Article  CAS  Google Scholar 

  20. Steward, O. & Falk, P.M. Selective localization of polyribosomes beneath developing synapses: a quantitative analysis of the relationships between polyribosomes and developing synapses in the hippocampus and dentate gyrus. J. Comp. Neurol. 314, 545–557 (1991).

    Article  CAS  PubMed Central  Google Scholar 

  21. Fiala, J.C., Feinberg, M., Popov, V. & Harris, K.M. Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J. Neurosci. 18, 8900–8911 (1998).

    Article  CAS  Google Scholar 

  22. Kullmann, D.M. Excitatory synapses. Neither too loud nor too quiet. Nature 399, 111–112 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. 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  Google Scholar 

  25. Aravanis, A.M., Pyle, J.L. & Tsien, R.W. Single synaptic vesicles fusing transiently and successively without loss of identity. Nature 423, 643–647 (2003).

    Article  CAS  Google Scholar 

  26. Gandhi, S.P. & Stevens, C.F. Three modes of synaptic vesicular recycling revealed by single-vesicle imaging. Nature 423, 607–613 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Kullmann, D.M. Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: implications for long-term potentiation. Neuron 12, 1111–1120 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Petralia, R.S. et al. Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nat. Neurosci. 2, 31–36 (1999).

    Article  CAS  Google Scholar 

  32. 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 Central  Google Scholar 

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

    Article  CAS  PubMed Central  Google Scholar 

  34. 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 Central  Google Scholar 

  35. 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 Central  Google Scholar 

  36. Li, P. & Zhuo, M. Silent glutamatergic synapses and nociception in mammalian spinal cord. Nature 393, 695–698 (1998).

    Article  CAS  PubMed Central  Google Scholar 

  37. 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 Central  Google Scholar 

  38. 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  Google Scholar 

  39. Cossart, R. et al. Quantal release of glutamate generates pure kainate and mixed AMPA/kainate EPSCs in hippocampal neurons. Neuron 35, 147–159 (2002).

    Article  CAS  Google Scholar 

  40. Yin, H.Z., Sensi, S.L., Carriedo, S.G. & Weiss, J.H. Dendritic localization of Ca2+-permeable AMPA/kainate channels in hippocampal pyramidal neurons. J. Comp. Neurol. 409, 250–260 (1999).

    Article  CAS  Google Scholar 

  41. Kumar, S.S., Bacci, A., Kharazia, V. & Huguenard, J.R. A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons. J. Neurosci. 22, 3005–3015 (2002).

    Article  CAS  Google Scholar 

  42. Poncer, J.C. & Malinow, R. Postsynaptic conversion of silent synapses during LTP affects synaptic gain and transmission dynamics. Nat. Neurosci. 4, 989–996 (2001).

    Article  CAS  Google Scholar 

  43. Tardin, C., Cognet, L., Bats, C., Lounis, B. & Choquet, D. Direct imaging of lateral movements of AMPA receptors inside synapses. Embo J. 22, 4656–4665 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  44. Choquet, D. & Triller, A. The role of receptor diffusion in the organization of the postsynaptic membrane. Nat. Rev. Neurosci. 4, 251–265 (2003).

    Article  CAS  Google Scholar 

  45. Zhou, Q., Xiao, M. & Nicoll, R.A. Contribution of cytoskeleton to the internalization of AMPA receptors. Proc. Natl. Acad. Sci. USA 98, 1261–1266 (2001).

    Article  CAS  Google Scholar 

  46. Blanpied, T.A., Scott, D.B. & Ehlers, M.D. Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron 36, 435–449 (2002).

    Article  CAS  Google Scholar 

  47. Bredt, D.S. & Nicoll, R.A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Swedish Medical Research Council (projects 01580, 12600 and 14842), Göteborgs Läkaresällskap, Åke Wibergs Stiftelse, Svenska Läkaresällskapet and Hjärnfonden. We thank J. Strandberg for participating in initial experiments and L. Groc for helpful discussions.

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Authors and Affiliations

  1. Department of Physiology, Institute of Physiology and Pharmacology, Göteborg University, Box 432, Göteborg, 405 30, Sweden

    Min-Yi Xiao, Pontus Wasling, Eric Hanse & Bengt Gustafsson

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Correspondence to Min-Yi Xiao.

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Xiao, MY., Wasling, P., Hanse, E. et al. Creation of AMPA-silent synapses in the neonatal hippocampus. Nat Neurosci 7, 236–243 (2004). https://doi.org/10.1038/nn1196

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