Article | Published:

NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay



Although long-term potentiation (LTP) is long-lasting, it is not permanent and decays within weeks after its induction. Little is known about the processes underlying this decay. Here we assessed the contribution of synaptic activity to LTP decay by determining the effect of the competitive NMDA receptor antagonist CPP on the decay of perforant path–dentate LTP. CPP blocked decay over a one-week period when administered daily following the induction of LTP, and blocked decay of the late, protein-synthesis-dependent phase of LTP when administered two days after LTP induction. CPP administered for a five-day period following spatial memory training enhanced subsequent memory retention. These data suggest that LTP is normally a persistent process that is actively reversed by NMDA receptor activation, and that both the early and late phases of LTP are dynamic processes regulated by NMDA receptors. These data also support the view that LTP is involved in maintaining spatial memory.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Bliss, T. V. P. & 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).

  2. 2

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

  3. 3

    Barnes, C. A. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J. Comp. Physiol. Psychol. 93, 74–104 (1979).

  4. 4

    Krug, M., Lossner, B. & Ott, T. Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats. Brain Res. Bull. 13, 39–42 (1984).

  5. 5

    Otani, S., Marshall, C. J., Tate, W. P., Goddard, G. V. & Abraham, W. C. Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not messenger RNA synthesis immediately post-tetanization. Neuroscience 28, 519–526 (1989).

  6. 6

    Nguyen, P. V. & Kandel, E. R. A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. J. Neurosci. 16, 3189–3198 (1996).

  7. 7

    Bailey, C. H. et al. Toward a molecular definition of long-term memory storage. Proc. Natl. Acad. Sci. USA 93, 13445–13452 (1996).

  8. 8

    Morris, R. G. M., Davis, S. & Butcher, S. P. in Long-term Potentiation: A Debate of the Current Issues (eds. J. L. Davis & M. Baudry) 267–300 (MIT Press, Cambridge, Massachusetts, 1991).

  9. 9

    Strack, S., Barban, M. A., Wadzinski, B. E. & Colbran, R. J. Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A. J. Neurochem. 68, 2119–2128 (1997).

  10. 10

    Lee, H. K., Kameyama, K., Huganir, R. L. & Bear, M. F. NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21, 1151–1162 (1998).

  11. 11

    Xiao, M. Y., Niu, Y. P. & Wigstrom, H. Activity-dependent decay of early LTP revealed by dual EPSP recording in hippocampal slices from young rats. Eur. J. Neurosci. 9, 1916–1923 (1996).

  12. 12

    Abraham, W. C. & Mason, S. E. Effects of the NMDA receptor/channel antagonists CPP and MK801 on hippocampal field potentials and long-term potentiation in anesthetized rats. Brain Res. 462, 40–46 (1988).

  13. 13

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

  14. 14

    Desmond, N. L., Colbert, C. M., Zhang, D. X. & Levy, W. B. NMDA receptor antagonists block the induction of long-term depression in the hippocampal dentate gyrus of the anesthetized rat. Brain Res. 552, 93–98 (1991).

  15. 15

    Christie, B. R. & Abraham, W. C. NMDA-dependent heterosynaptic long-term depression in the dentate gyrus of anaesthetized rats. Synapse 10, 1–6 (1992).

  16. 16

    Desmond, N. L. & Levy, W. B. Synaptic correlates of associative potentiation/depression: an ultrastructural study in the hippocampus. Brain Res. 265, 21–30 (1983).

  17. 17

    Abraham, W. C. & Goddard, G. V. Asymmetric relationships between homosynaptic long-term potentiation and heterosynaptic long-term depression. Nature 305, 717–719 (1983).

  18. 18

    Kulla, A., Reymann, K. G. & Manahan-Vaughan, D. Time-dependent induction of depotentiation in the dentate gyrus of freely moving rats: involvement of group 2 metabotropic glutamate receptors. Eur. J. Neurosci. 11, 3864–3872 (1999).

  19. 19

    Martin, S. J. Time-dependent reversal of dentate LTP by 5 Hz stimulation. Neuroreport 9, 3775–3781 (1998).

  20. 20

    Levy, W. B. & Steward, O. Synapses as associative memory elements in the hippocampal formation. Brain Res. 175, 233–245 (1979).

  21. 21

    Doyere, V., Srebro, B. & Laroche, S. Heterosynaptic LTD and depotentiation in the medial perforant path of the dentate gyrus in the freely moving rat. J. Neurophysiol. 77, 571–578 (1997).

  22. 22

    Xu, L., Anwyl, R. & Rowan, M. J. Spatial exploration induces a persistent reversal of long-term potentiation in rat hippocampus. Nature 394, 891–894 (1998).

  23. 23

    Shors, T. J. & Matzel, L. D. Long-term potentiation: what's learning got to do with it? Behav. Brain Sci. 20, 597–614 (1997).

  24. 24

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

  25. 25

    Barnes, C. A., Danysz, W. & Parsons, C. G. Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur. J. Neurosci. 8, 565–571 (1996).

  26. 26

    Norris, C. M. & Foster, T. C. MK-801 improves retention in aged rats: implications for altered neural plasticity in age-related memory deficits. Neurobiol. Learn. Mem. 71, 194–206 (1999).

  27. 27

    Ebbinghaus, H. Memory: A Contribution to Experimental Psychology Über das Gedchtnis (Columbia Univ. Press, New York, 1913) (translated from Untersuchungen zur experimentellen Psychologie, Duncker & Humblot, Leipzig, Germany, 1885).

  28. 28

    Thorndike, E. L. The law of effect. Am. J. Psych. 39, 212–222 (1927).

  29. 29

    Christie, B. R. & Abraham, W. C. Priming of associative long-term depression in the dentate gyrus by theta frequency synaptic activity. Neuron 9, 79–84 (1992).

  30. 30

    Lambert, J. D. & Jones, R. S. A reevaluation of excitatory amino acid-mediated synaptic transmission in rat dentate gyrus. J. Neurophysiol. 4, 119–132 (1990).

  31. 31

    Barnes, C. A. & McNaughton, B. L. An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses. Behav. Neurosci. 99, 1040–1048 (1985).

  32. 32

    Laroche, S., Doyere, V. & Bloch, V. Linear relation between the magnitude of long-term potentiation in the dentate gyrus and associative learning in the rat. A demonstration using commissural inhibition and local infusion of an N-methyl-d-aspartate receptor antagonist. Neuroscience 28, 375–386 (1989).

  33. 33

    Morris, R. G. M., Anderson, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986).

  34. 34

    Malleret, G. et al. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104, 675–686 (2001).

  35. 35

    Paxinos, G. & Watson, C. Stereotaxic Atlas of the Rat Brain (Academic, New York, 1982).

  36. 36

    Staubli, U. & Lynch, G. Stable hippocampal long-term potentiation elicited by 'theta' pattern stimulation. Brain Res. 435, 227–234 (1987).

  37. 37

    Olton, D. S., Collison, C. & Werz, M. A. Spatial memory and radial arm maze performance in rats. Learn. Motiv. 8, 289–314 (1977).

Download references


The authors thank C. Wilson and B.J. Claiborne for comments on the manuscript, J. Bustamante, J. Burrell and B. Agrawal for technical support, and A. Gulledge for suggesting tests of spatial memory. Supported by NIDA (DA01983).

Author information

Competing interests

The authors declare no competing financial interests.

Correspondence to Brian E. Derrick.

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

Further reading

Figure 1: Efficacy of a 10-mg/kg dose of the NMDA receptor antagonist CPP on LTP induced 12 and 24 h following administration.
Figure 2: Administration of CPP blocks LTP decay.
Figure 3: CPP blocks the decay of late-phase LTP.
Figure 4: CPP enhances retention of spatial memory.