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LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite

Abstract

Structural remodelling of synapses1,2,3,4 and formation of new synaptic contacts5,6,7,8 has been postulated as a possible mechanism underlying the late phase of long-term potentiation (LTP), a form of plasticity which is involved in learning and memory9. Here we use electron microscopy to analyse the morphology of synapses activated by high-frequency stimulation and identified by accumulated calcium in dendritic spines. LTP induction resulted in a sequence of morphological changes consisting of a transient remodelling of the postsynaptic membrane followed by a marked increase in the proportion of axon terminals contacting two or more dendritic spines. Three-dimensional reconstruction revealed that these spines arose from the same dendrite. As pharmacological blockade of LTP prevented these morphological changes, we conclude that LTP is associated with the formation of new, mature and probably functional synapses contacting the same presynaptic terminal and thereby duplicating activated synapses.

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Figure 1: Labelling of activated spine profiles by induction of LTP.
Figure 2: Time course of ultrastructural changes associated with LTP induction.
Figure 3: Blockade of LTP prevents morphological changes.
Figure 4: Three-dimensional reconstruction of multiple spine boutons.

References

  1. Calverley,R. K. & Jones,D. G. Contributions of dendritic spines and perforated synapses to synaptic plasticity. Brain Res. Brain Res. Rev. 15, 215–249 (1990).

    Article  CAS  Google Scholar 

  2. Geinisman,Y., Detoledo-Morrell,L. & Morrell,F. Induction of long-term potentiation is associated with an increase in the number of axospinous synapses with segmented postsynaptic densities. Brain Res. 566, 77–88 (1991).

    Article  CAS  Google Scholar 

  3. Geinisman,Y. et al. Structural synaptic correlate of long-term potentiation: formation of axospinous synapses with multiple, completely partitioned transmission zones. Hippocampus 3, 435–445 (1993).

    Article  CAS  Google Scholar 

  4. Buchs,P. A. & Muller,D. Induction of long-term potentiation is associated with major ultrastructural changes of activated synapses. Proc. Natl Acad. Sci. USA 93, 8040–8045 (1996).

    Article  ADS  CAS  Google Scholar 

  5. Geinisman,Y., Detoledo-Morrell,L., Morrell,F., Persina,I. S. & Beatty,M. A. Synapse restructuring associated with the maintenance phase of hippocampal long-term potentiation. J. Comp. Neurol. 368, 413–423 (1996).

    Article  CAS  Google Scholar 

  6. Bolshakov,V. Y., Golan,H., Kandel,E. R. & Siegelbaum,S. A. Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3-CA1 synapses in the hippocampus. Neuron 19, 635–651 (1997).

    Article  CAS  Google Scholar 

  7. Maletic-Savatic,M., Malinow,R. & Svoboda,K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923–1927 (1999).

    Article  ADS  CAS  Google Scholar 

  8. Engert,F. & Bonhoeffer,T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999).

    Article  ADS  CAS  Google Scholar 

  9. 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 

  10. Sorra,K. E., Fiala,J. C. & Harris,K. M. Critical assessment of the involvement of perforations, spinules, and spine branching in hippocampal synapse formation. J. Comp. Neurol. 398, 225–240 (1998).

    Article  CAS  Google Scholar 

  11. Buchs,P. A., Stoppini,L., Parducz,A., Siklos,L. & Muller,D. A new cytochemical method for the ultrastructural localization of calcium in the central nervous system. J. Neurosci. Methods 54, 83–93 (1994).

    Article  CAS  Google Scholar 

  12. 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. 13, 3736–3748 (1993).

    Article  CAS  Google Scholar 

  13. 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. 17, 190–203 (1997).

    Article  CAS  Google Scholar 

  14. McKinney,R. A., Capogna,M., Durr,R., Gahwiler,B. H. & Thompson,S. M. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nature Neurosci. 2, 44–49 (1999).

    Article  CAS  Google Scholar 

  15. 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 

  16. Ziv,N. E. & Smith,S. J. Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron 17, 91–102 (1996).

    Article  CAS  Google Scholar 

  17. Trommald,M. & Hulleberg,G. Dimensions and density of dendritic spines from rat dentate granule cells based on reconstructions from serial electron micrographs. J. Comp. Neurol. 377, 15–28 (1997).

    Article  CAS  Google Scholar 

  18. Carlin,R. K. & Siekevitz,P. Plasticity in the central nervous system: do synapses divide? Proc. Natl Acad. Sci. USA 80, 3517–3521 (1983).

    Article  ADS  CAS  Google Scholar 

  19. Nieto-Sampedro,M., Hoff,S. F. & Cotman,C. W. Perforated postsynaptic densities: probable intermediates in synapse turnover. Proc. Natl Acad. Sci. USA 79, 5718–5722 (1982).

    Article  ADS  CAS  Google Scholar 

  20. Fischer,M., Kaech,S., Knutti,D. & Matus,A. Rapid actin-based plasticity in dendritic spines. Neuron 20, 847–854 (1998).

    Article  CAS  Google Scholar 

  21. Shi,S. H. et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811–1816 (1999).

    Article  CAS  Google Scholar 

  22. Liao,D., Zhang,X., O'Brien,R., Ehlers,M. D. & Huganir,R. L. Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons. Nature Neurosci. 2, 37–43 (1999).

    Article  CAS  Google Scholar 

  23. Woolley,C. S., Wenzel,H. J. & Schwartzkroin,P. A. Estradiol increases the frequency of multiple synapse boutons in the hippocampal CA1 region of the adult female rat. J. Comp. Neurol. 373, 108–117 (1996).

    Article  CAS  Google Scholar 

  24. Kirov,S. A., Sorra,K. E. & Harris,K. M. Slices have more synapses than perfusion-fixed hippocampus from both young and mature rats. J. Neurosci. 19, 2876–2886 (1999).

    Article  CAS  Google Scholar 

  25. Moser,M. B., Trommald,M. & Andersen,P. An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc. Natl Acad. Sci. USA 91, 12673–12675 (1994).

    Article  ADS  CAS  Google Scholar 

  26. Kleim,J. A., Vij,K., Ballard,D. H. & Greenough,W. T. Learning-dependent synaptic modifications in the cerebellar cortex of the adult rat persists for at least four weeks. J. Neurosci. 17, 717–721 (1997).

    Article  CAS  Google Scholar 

  27. Stoppini,L., Buchs,P. A. & Muller,D. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173–182 (1991).

    Article  CAS  Google Scholar 

  28. Sterio,D. C. The unbiased estimation of number and sizes of arbitrary particles using the disector. J. Microsc. 134, 127–136 (1984).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank L. M. Cruz-Orive for advice on stereology; K. Harris for 3D reconstruction software; D. Smithies for morphometry software on AVS; L. Parisi and M. Moosmayer for culture preparation and technical assistance; and F. Pillonel for photographic work. This work was supported by the Swiss National Science Foundation, the Human Frontier Science Program, the National Priority Program and the Jean-Falk Vairant Foundation.

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Correspondence to D. Muller.

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Toni, N., Buchs, PA., Nikonenko, I. et al. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999). https://doi.org/10.1038/46574

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