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Distributed synaptic modification in neural networks induced by patterned stimulation


Activity-dependent changes in synaptic efficacy or connectivity are critical for the development1, signal processing2 and learning and memory functions3,4,5,6 of the nervous system. Repetitive correlated spiking of pre- and postsynaptic neurons can induce a persistent increase or decrease in synaptic strength, depending on the timing of the pre- and postsynaptic excitation7,8,9,10,11,12,13. Previous studies on such synaptic modifications have focused on synapses made by the stimulated neuron. Here we examine, in networks of cultured hippocampal neurons, whether and how localized stimulation can modify synapses that are remote from the stimulated neuron. We found that repetitive paired-pulse stimulation of a single neuron for brief periods induces persistent strengthening or weakening of specific polysynaptic pathways in a manner that depends on the interpulse interval. These changes can be accounted for by correlated pre- and postsynaptic excitation at distant synaptic sites, resulting from different transmission delays along separate pathways. Thus, through such a ‘delay-line’ mechanism, temporal information coded in the timing of individual spikes14,15,16,17 can be converted into and stored as spatially distributed patterns of persistent synaptic modifications in a neural network.

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Figure 1: Polysynaptic pathways in a network of cultured hippocampal neurons.
Figure 2: Pathway remodelling induced by repetitive paired-pulse stimulation (PPS).
Figure 3: Pathway remodelling induced by correlated excitation through transmission delay.
Figure 4: Modifications of remote excitatory synapses by correlated spiking.


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

    Article  ADS  CAS  Google Scholar 

  2. Abbott,L. F., Varela,J. A., Sen,K. & Nelson,S. B. Synaptic depression and cortical gain control. Science 275, 220–224 (1997).

    Article  CAS  Google Scholar 

  3. Squire,L. R. Memory and Brain (Oxford Univ. Press, New York, 1987).

    Google Scholar 

  4. Churchland,P. S. & Sejnowski,T J. the Computational Brain (The MIT Press, Cambridge, MA, 1992).

    MATH  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  6. Goda,Y. & Stevens,C. F. Synaptic plasticity: the basis of particular types of learning. Curr. Biol. 6, 375–378 (1996).

    Article  CAS  Google Scholar 

  7. Levy,W. B. & Steward,O. Temporal contiguity requirements for long-term associative potentiation/depression in the hippocampus. Neuroscience 8, 791–797 (1983).

    Article  CAS  Google Scholar 

  8. Markram,H., Lubke,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 

  9. Magee,J. C. & Johnston,D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275, 209–213 (1997).

    Article  CAS  Google Scholar 

  10. Bell,C. C., Han,V. Z., Sugawara,Y. & Grant,K. Synaptic plasticity in a cerebellum-like structure depends on temporal order. Nature 387, 278–281 (1997).

    Article  ADS  CAS  Google Scholar 

  11. 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. (Lond.) 507, 237–247 (1998).

    Article  CAS  Google Scholar 

  12. Zhang,L. I., Tao,H. W., Holt,C. E., Harris,W. A. & Poo,M.-m. A critical window for cooperation and competition among developing retinotectal synapses. Nature 395, 37–44 (1998).

    Article  ADS  CAS  Google Scholar 

  13. 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 

  14. Hopfield,J. J. Pattern recognition computation using action potential timing for stimulus representation. Nature 376, 33–36 (1995).

    Article  ADS  CAS  Google Scholar 

  15. Singer,W. & Gray,C. M. Visual feature integration and the temporal correlation hypothesis. Annu. Rev. Neurosci. 18, 555–86 (1995).

    Article  CAS  Google Scholar 

  16. Gerstner,W., Kempter,R., van Hemmen,J. L. & Wagner,H. A neuronal learning rule for sub-millisecond temporal coding. Nature 383, 76–81 (1996).

    Article  ADS  CAS  Google Scholar 

  17. Strong,S. P., Koberle,R., De Ruyter Van Steveninck,R. R. & Bialek,W. Entropy and information in neural spike trains. Phys. Rev. Lett. 80, 197–200 (1998).

    Article  ADS  CAS  Google Scholar 

  18. Malenka,R. C. & Nicoll,R. A. NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 16, 521–527 (1993).

    Article  CAS  Google Scholar 

  19. Linden,D. J. & Connor,J. A. Long-term synaptic depression. Annu. Rev. Neurosci. 18, 319–357 (1995).

    Article  CAS  Google Scholar 

  20. Miles,R. & Wong,R. K. Latent synaptic pathways revealed after tetanic stimulation in the hippocampus. Nature 329, 724–726 (1987).

    Article  ADS  CAS  Google Scholar 

  21. Turrigiano,G., Abbott,L. F. & Marder,E. Activity-dependent changes in the intrinsic properties of cultured neurons. Science 264, 974–977 (1994).

    Article  ADS  CAS  Google Scholar 

  22. Buzsàki,G. Polysynaptic long-term potentiation: a physiological role of the perforant path–CA3/CA1 pyramidal cell synapse. Brain Res. 455, 192–195 (1988).

    Article  Google Scholar 

  23. Buonomano,D. V., Hickmott,P. W. & Merzenich,M. M. Context-sensitive synaptic plasticity and temporal-to-spatial transformations in hippocampal slices. Proc. Natl Acad. Sci. USA 94, 10403–10408 (1997).

    Article  ADS  CAS  Google Scholar 

  24. Carr,C. E. & Konishi,M. A circuit for detection of interaural time differences in the brain stem of the barn owl. J. Neurosci. 10, 3227–3246 (1990).

    Article  CAS  Google Scholar 

  25. Kristan,W. B J. He's got rhythm: single neurons signal timing on a scale of seconds. Nature Neurosci. 1, 643–645 (1998).

    Article  CAS  Google Scholar 

  26. Tank,D. W. & Hopfield,J. J. Neural computation by concentrating information in time. Proc. Natl Acad. Sci. USA 84, 1896–1900 (1987).

    Article  ADS  MathSciNet  CAS  Google Scholar 

  27. Moore,J. W., Choi,J.-S. & Brunzell,D. H. in Timing of Behaviour (eds Risenbaum, D. A. & Collyer, C. E.) 3–34 (MIT Press, Cambridge, MA, 1998).

    Google Scholar 

  28. Abeles,M. Corticonics (Cambridge Univ. Press, Cambridge, 1991).

    Book  Google Scholar 

  29. Fitzsimonds,R. M., Song,H. J. & Poo,M.-m. Propagation of activity-dependent synaptic depression in simple neural networks. Nature 388, 439–448 (1997).

    Article  ADS  CAS  Google Scholar 

  30. Rae,J., Cooper,K., Gates,P. & Watsky,M. Low access resistance perforated patch recordings using amphotericin B. J. Neurosci. Methods 37, 15–26 (1991).

    Article  CAS  Google Scholar 

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We thank X. Wang for culture preparations and B. Berninger, W. Kristan, L. Zhang, A. Schinder and S. Andersen for helpful discussions and comments on the manuscript. Supported by grants from NIH (M.P.) and a President's Postdoctoral Fellowship from the University of California and a training grant from NIH (G.B.).

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Correspondence to Guo-qiang Bi.

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Bi, Gq., Poo, Mm. Distributed synaptic modification in neural networks induced by patterned stimulation. Nature 401, 792–796 (1999).

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