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Conservation of total synaptic weight through balanced synaptic depression and potentiation


Memory is believed to depend on activity-dependent changes in the strength of synapses1. In part, this view is based on evidence that the efficacy of synapses can be enhanced or depressed depending on the timing of pre- and postsynaptic activity2,3,4,5. However, when such plastic synapses are incorporated into neural network models, stability problems may develop because the potentiation or depression of synapses increases the likelihood that they will be further strengthened or weakened6. Here we report biological evidence for a homeostatic mechanism that reconciles the apparently opposite requirements of plasticity and stability. We show that, in intercalated neurons of the amygdala, activity-dependent potentiation or depression of particular glutamatergic inputs leads to opposite changes in the strength of inputs ending at other dendritic sites. As a result, little change in total synaptic weight occurs, even though the relative strength of inputs is modified. Furthermore, hetero- but not homosynaptic alterations are blocked by intracellular dialysis of drugs that prevent Ca2+ release from intracellular stores. Thus, in intercalated neurons at least, inverse heterosynaptic plasticity tends to compensate for homosynaptic long-term potentiation and depression, thus stabilizing total synaptic weight.

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Figure 1: Experimental approach.
Figure 2: LTD induction produces heterosynaptic LTP.
Figure 3: LTP induction produces heterosynaptic LTD.
Figure 4: Ca2+ release from intracellular stores is required for the conservation of total synaptic weight.


  1. Martin, S. J., Grimwood, P. D. & Morris, R. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000)

    Article  CAS  Google Scholar 

  2. Markram, H., Lübke, J., Frotscher, M. & Sakmann, B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275, 213–215 (1997)

    Article  CAS  Google Scholar 

  3. Bi, G. Q. & Poo, M. M. Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. J. Neurosci. 18, 10464–10472 (1998)

    Article  CAS  Google Scholar 

  4. Debanne, D., Gähwiler, B. H. & Thompson, S. M. Long-term synaptic plasticity between pairs of individual CA3 pyramidal cells in rat hippocampal slice cultures. J. Physiol. (Lond.) 507, 237–247 (1998)

    Article  CAS  Google Scholar 

  5. Feldman, D. E. Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in rat barrel cortex. Neuron 27, 45–56 (2000)

    Article  CAS  Google Scholar 

  6. Abbott, L. F. & Nelson, S. B. Synaptic plasticity: taming the beast. Nature Neurosci. 3, 1178–1183 (2000)

    Article  CAS  Google Scholar 

  7. Arbib, M. A. The Handbook of Brain Theory and Neural Networks (MIT Press, Cambridge, Massachusetts, 1995)

    Google Scholar 

  8. Royer, S. & Paré, D. Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses. Neuroscience 115, 455–462 (2002)

    Article  CAS  Google Scholar 

  9. Rall, W. in Methods in Neuronal Modeling: From Synapses to Networks (eds Koch, C. & Segev, I.) 9–62 (MIT Press, Cambridge, Massachusetts, 1989)

    Google Scholar 

  10. Holm, S. A simple sequentially rejective multiple test procedure. Scand. J. Stat. 6, 65–70 (1979)

    MathSciNet  MATH  Google Scholar 

  11. Emptage, N., Bliss, T. Y. & Fine, A. Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines. Neuron 22, 115–124 (1999)

    Article  CAS  Google Scholar 

  12. Liang, Y., Yuan, L. L., Johnston, D. & Gray, R. Calcium signaling at single mossy fiber presynaptic terminals in the rat hippocampus. J. Neurophysiol. 87, 1132–1137 (2002)

    Article  CAS  Google Scholar 

  13. Nishiyama, M., Hong, K., Mikoshiba, K., Poo, M. M. & Kato, K. Calcium stores regulate the polarity and input specificity of synaptic modifications. Nature 408, 584–588 (2000)

    Article  ADS  CAS  Google Scholar 

  14. Demaurex, N., Lew, D. P. & Krause, K.-H. Cyclopiazonic acid depletes intracellular Ca2+ stores and activates an influx pathway for divalent cations in HL-60 cells. J. Biol. Chem. 267, 2318–2324 (1992)

    CAS  PubMed  Google Scholar 

  15. Xu, L., Tripathy, A., Pasek, D. A. & Meissner, G. Ruthenium red modifies the cardiac and skeletal muscle Ca2+ release channels (ryanodine receptors) by multiple mechanisms. J. Biol. Chem. 274, 32680–32691 (1999)

    Article  CAS  Google Scholar 

  16. Lynch, G. S., Dunwiddie, T. & Gribkoff, V. Heterosynaptic depression: a postsynaptic correlate of long-term potentiation. Nature 266, 737–739 (1977)

    Article  ADS  CAS  Google Scholar 

  17. Abraham, W. C. & Wickens, J. R. Heterosynaptic long-term depression is facilitated by blockade of inhibition in area CA1 of the hippocampus. Brain Res. 546, 336–340 (1991)

    Article  CAS  Google Scholar 

  18. Scanziani, M., Malenka, R. C. & Nicoll, R. A. Role of intercellular interactions in heterosynaptic long-term depression. Nature 380, 446–450 (1996)

    Article  ADS  CAS  Google Scholar 

  19. Coussens, C. M. & Teyler, T. J. Long-term potentiation induces synaptic plasticity at nontetanized adjacent synapses. Learn. Mem. 3, 106–114 (1996)

    Article  CAS  Google Scholar 

  20. Muller, D., Hefft, S. & Figurov, A. Heterosynaptic interactions between LTP and LTD in CA1 hippocampal slices. Neuron 14, 599–605 (1995)

    Article  CAS  Google Scholar 

  21. Malenka, R. C. Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78, 535–538 (1994)

    Article  CAS  Google Scholar 

  22. Bliss, T. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993)

    Article  ADS  CAS  Google Scholar 

  23. Bear, M. F. & Abraham, W. C. Long-term depression in hippocampus. Annu. Rev. Neurosci. 19, 437–462 (1996)

    Article  CAS  Google Scholar 

  24. Soderling, T. R. & Derkach, V. A. Postsynaptic protein phosphorylation and LTP. Trends Neurosci. 23, 75–80 (2000)

    Article  CAS  Google Scholar 

  25. Winder, D. G. & Sweatt, J. D. Roles of serine/threonine phosphatases in hippocampal synaptic plasticity. Nature Rev. Neurosci. 2, 461–474 (2001)

    Article  CAS  Google Scholar 

  26. Carroll, R. C., Beattie, E. C., von Zastrow, M. & Malenka, R. C. Role of AMPA receptor endocytosis in synaptic plasticity. Nature Rev. Neurosci. 2, 315–324 (2001)

    Article  CAS  Google Scholar 

  27. Turrigiano, G. G. Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci. 22, 221–227 (1999)

    Article  CAS  Google Scholar 

  28. Song, S., Miller, K. D. & Abbott, L. F. Competitive Hebbian learning through spike-timing-dependent synaptic plasticity. Nature Neurosci. 3, 919–926 (2000)

    Article  CAS  Google Scholar 

  29. Markram, H. & Tsodyks, M. Redistribution of synaptic efficacy between neocortical pyramidal neurons. Nature 382, 807–810 (1996)

    Article  ADS  CAS  Google Scholar 

  30. O'Donnovan, M. J. & Rinzel, J. Synaptic depression: a dynamic regulator of synaptic communication with varied functional roles. Trends Neurosci. 20, 431–433 (1997)

    Article  Google Scholar 

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This work was supported by the National Science Foundation, the Canadian Institutes of Health Research and the Center for Molecular and Behavioral Neuroscience of Rutgers University. We thank Dr E. J. Lang for comments on the manuscript.

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Correspondence to Denis Paré.

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Supplementary information


Supplementary Information: contains two tables summarizing the average changes in response amplitude seen in various conditions (control, AP5, BAPTA, RR and CPA) at the induction site and heterosynaptic sites. (PDF 5 kb)

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Royer, S., Paré, D. Conservation of total synaptic weight through balanced synaptic depression and potentiation. Nature 422, 518–522 (2003).

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