Letter | Published:

Structural basis of long-term potentiation in single dendritic spines


Dendritic spines of pyramidal neurons in the cerebral cortex undergo activity-dependent structural remodelling1,2,3,4,5 that has been proposed to be a cellular basis of learning and memory6. How structural remodelling supports synaptic plasticity4,5, such as long-term potentiation7, and whether such plasticity is input-specific at the level of the individual spine has remained unknown. We investigated the structural basis of long-term potentiation using two-photon photolysis of caged glutamate at single spines of hippocampal CA1 pyramidal neurons8. Here we show that repetitive quantum-like photorelease (uncaging) of glutamate induces a rapid and selective enlargement of stimulated spines that is transient in large mushroom spines but persistent in small spines. Spine enlargement is associated with an increase in AMPA-receptor-mediated currents at the stimulated synapse and is dependent on NMDA receptors, calmodulin and actin polymerization. Long-lasting spine enlargement also requires Ca2+/calmodulin-dependent protein kinase II. Our results thus indicate that spines individually follow Hebb's postulate for learning. They further suggest that small spines are preferential sites for long-term potentiation induction, whereas large spines might represent physical traces of long-term memory.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Van Harreveld, A. & Fifkova, E. Swelling of dendritic spines in the fascia dentata after stimulation of the perforant fibers as a mechanism of post-tetanic potentiation. Exp. Neurol. 49, 736–749 (1975)

  2. 2

    Trachtenberg, J. T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794 (2002)

  3. 3

    Grutzendler, J., Kasthuri, N. & Gan, W. B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002)

  4. 4

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

  5. 5

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

  6. 6

    Yuste, R. & Bonhoeffer, T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071–1089 (2001)

  7. 7

    Bliss, T. V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. (Lond.) 232, 331–356 (1973)

  8. 8

    Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nature Neurosci. 4, 1086–1092 (2001)

  9. 9

    Malenka, R. C. et al. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340, 554–557 (1989)

  10. 10

    Malinow, R., Schulman, H. & Tsien, R. W. Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245, 862–866 (1989)

  11. 11

    Krucker, T., Siggins, G. R. & Halpain, S. Dynamic actin filaments are required for stable long-term potentiation (LTP) in area CA1 of the hippocampus. Proc. Natl Acad. Sci. USA 97, 6856–6861 (2000)

  12. 12

    Davies, S. N., Lester, R. A., Reymann, K. G. & Collingridge, G. L. Temporally distinct pre- and post-synaptic mechanisms maintain long-term potentiation. Nature 338, 500–503 (1989)

  13. 13

    Horn, R. & Marty, A. Muscarinic activation of ionic currents measured by a new whole-cell recording method. J. Gen. Physiol. 92, 145–159 (1988)

  14. 14

    Cormier, R. J., Mauk, M. D. & Kelly, P. T. Glutamate iontophoresis induces long-term potentiation in the absence of evoked presynaptic activity. Neuron 10, 907–919 (1993)

  15. 15

    Kato, K., Clifford, D. B. & Zorumski, C. F. Long-term potentiation during whole-cell recording in rat hippocampal slices. Neuroscience 53, 39–47 (1993)

  16. 16

    Gustafsson, B. & Wigstrom, H. Long-term potentiation in the hippocampal CA1 region: its induction and early temporal development. Prog. Brain Res. 83, 223–232 (1990)

  17. 17

    Kim, C. H. & Lisman, J. E. A role of actin filament in synaptic transmission and long-term potentiation. J. Neurosci. 19, 4314–4324 (1999)

  18. 18

    Schnell, E. et al. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc. Natl Acad. Sci. USA 99, 13902–13907 (2002)

  19. 19

    Rumbaugh, G., Sia, G. M., Garner, C. C. & Huganir, R. L. Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons. J. Neurosci. 23, 4567–4576 (2003)

  20. 20

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

  21. 21

    Pak, D. T., Yang, S., Rudolph-Correia, S., Kim, E. & Sheng, M. Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron 31, 289–303 (2001)

  22. 22

    Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000)

  23. 23

    Lisman, J., Schulman, H. & Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nature Rev. Neurosci. 3, 175–190 (2002)

  24. 24

    Hebb, D. O. The Organization of Behavior (Wiley, New York, 1949)

  25. 25

    Yuste, R. & Denk, W. Dendritic spines as basic functional units of neuronal integration. Nature 375, 682–684 (1995)

  26. 26

    Engert, F. & Bonhoeffer, T. Synapse specificity of long-term potentiation breaks down at short distances. Nature 388, 279–284 (1997)

  27. 27

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

  28. 28

    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)

  29. 29

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

  30. 30

    Kasai, H., Matsuzaki, M., Noguchi, J., Yasumatsu, N. & Nakahara, H. Structure–stability–function relationships of dendritic spines. Trends Neurosci. 26, 360–368 (2003)

Download references


We thank P. Haydon for reading the manuscript, N. Takahashi and T. Kise for technical assistance and Y. Yanagawa and M. Okabe for the eGFP construct. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (H.K. and M.M.) and by the Human Frontier Science Program Organization (G.C.R.E.-D. and H.K.), the NIH (G.C.R.E.-D. and H.K.), the NSF (G.C.R.E.-D) and the McKnight Endowment Fund for Neuroscience (G.C.R.E.-D).

Author information

Correspondence to Haruo Kasai.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Information

This contains additional figures (Supplementary Figures 1-3) and descriptions of spine-head enlargement. (DOC 532 kb)

Supplementary Methods

This file describes supplementary methods for estimation of spine-head volume. (DOC 21 kb)

Supplementary Movie 1

This movie shows enlargement of the spine head shown in Figure 1a. The stacked images were acquired every 3 to 16 min. The horizontal white bar shows time of image acquisition. Each marker represents 30 min. Repetitive uncaging of MNI-glutamate was affected when the white square appears. (MP4 209 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading

Figure 1: Spine-head enlargement induced by repetitive uncaging of MNI-glutamate.
Figure 2: Properties of the spine-head enlargement.
Figure 3: Colocalization of enlargement of spine heads and potentiation of AMPA-receptor-mediated currents.
Figure 4: Relationship between spine-head enlargement and potentiation of AMPA-receptor-mediated currents.


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.