Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

NMDA receptors, place cells and hippocampal spatial memory

Key Points

  • As a main component of the medial temporal lobe, the hippocampus has been shown to be crucial for the formation of declarative memory in humans. In rodents, the hippocampus has several features that facilitate a multilevel analysis of its function: it is required for spatial learning, which can be directly assessed with tasks such as the Morris water maze task; it demonstrates changes in synaptic efficacy, such long-term potentiation (LTP), after high-frequency input; and individual hippocampal pyramidal cells fire in a place-specific manner as an animal moves through an environment, allowing direct observation of the quality of spatial encoding.

  • The N-methyl-D-aspartate receptor (NMDAR), which is highly expressed in the hippocampus, has been identified as an ideal molecular coincidence detector owing to its voltage-dependent magnesium block, high calcium permeability and slow activation and deactivation kinetics. The demonstration that the induction of hippocampal LTP depends on the activation of NMDARs further strengthened the link between LTP and Hebb's synaptic hypothesis for memory storage, in which modifications of synaptic efficacy by coincident input was the central theme

  • Both pharmacological and genetic approaches have shown that hippocampal NMDARs, particularly in region CA1, are required for the acquisition of spatial memories. Furthermore, deletion of NMDARs specifically in CA1 pyramidal cells leads to a loss of the coordinated activity of CA1 place cells, with overlapping fields and a disruption of the ensemble code for space.

  • NMDAR-mediated plasticity in the recurrent connections in area CA3 of the hippocampus is crucial for the rapid encoding of novel experiences, in a process that might be akin to episodic memory formation in humans. CA3-NR1-knockout mice are deficient in acquiring novel place/reward location information, and CA1 place cells in these mice were significantly impaired when recorded in a novel environment (with enlarged place fields and an augmented integrated firing rate).

  • Memory retrieval is an associative process that might involve recurrent network activation as a means of pattern completion — the recall of an entire memory based on exposure to a partial set of cues. A loss of synaptic plasticity in the recurrent collaterals of area CA3 prevents this form of memory retrieval, as assessed by a spatial learning task in CA3-NR1-knockout mice, and is manifested as uncoordinated, spatially less-tuned CA1 place-cell activity under partial-cue conditions.

  • Hippocampal place cells can be viewed as memory traces at the neuronal ensemble level, showing stable patterns of firing that can develop quickly and can be reactivated independently of behaviour. CA3-NR1-knockout mice have allowed the direct observation of a fourth important property of a putative memory trace — the experience-dependent formation of the spatial specificity of the fields.

  • Progress has been made in understanding the part that NMDARs play in hippocampal memory, both generally, and specifically in terms of where (which subfield/cell type) and when (which phase of memory) the receptors are needed. Furthermore, the development of genetic techniques, including inducible and reversible cell-type-specific gene activation, and the establishment of more refined behavioural and physiological analyses will lead to even deeper comprehension of the relationship between plasticity, memory and space in the hippocampus.

Abstract

N-methyl-D-aspartate receptors (NMDARs) in the rodent hippocampus have been shown to be essential for spatial learning and memory, and for the induction of long-term synaptic plasticity at various hippocampal synapses. In this review, we examine the evidence concerning the role of NMDARs in hippocampal memory processes, with an emphasis on the function of NMDARs in area CA1 of the hippocampus in memory acquisition, and the unique role of NMDARs in area CA3 in the rapid acquisition and associative retrieval of spatial information. Finally, we discuss the data that have emerged from in vivo hippocampal recording studies that indicate that the activity of hippocampal place cells during behaviour is an expression of a memory trace.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Connections in the corticohippocampal network.
Figure 2: CA3-NR1-knockout mice are impaired in delayed matching-to-place task in water maze.
Figure 3: Impaired rapid formation of CA1 place fields as a consequence of CA3 NMDAR knockout.
Figure 4: Spatial pattern completion model in hippocampal networks.

References

  1. Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21 (1957).

    Article  CAS  Google Scholar 

  2. Schmolck, H., Kensinger, E. A., Corkin, S. & Squire, L. R. Semantic knowledge in patient H. M. and other patients with bilateral medial and lateral temporal lobe lesions. Hippocampus 12, 520–533 (2002).

    Article  PubMed  Google Scholar 

  3. Rempel-Clower, N. L., Zola, S. M., Squire, L. R. & Amaral, D. G. Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation. J. Neurosci. 16, 5233–5255 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Zola, S. M. & Squire, L. R. Relationship between magnitude of damage to the hippocampus and impaired recognition memory in monkeys. Hippocampus 11, 92–98 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Jarrard, L. E. On the role of the hippocampus in learning and memory in the rat. Behav. Neural Biol. 60, 9–26 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Morris, R. G. M., Garrud, P., Rawlins, J. N. P. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).

    Article  CAS  PubMed  Google Scholar 

  7. Silva, A. J., Giese, K. P., Fedorov, N. B., Frankland, P. W. & Kogan, J. H. Molecular, cellular, and neuroanatomical substrates of place learning. Neurobiol. Learn. Mem. 70, 44–61 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. O'Keefe, J. & Dostrovsky, J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 34, 171–175 (1971).

    Article  CAS  PubMed  Google Scholar 

  9. Bliss, T. V. P. & Lømo, 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).

    Article  CAS  Google Scholar 

  10. Hebb, D. O. The Organization of Behavior: A Neuropsychological Theory (John Wiley, New York, 1949).

    Google Scholar 

  11. Collingridge, G. L., Kehl, S. J. & McLennon, H. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J. Physiol. (Lond.) 334, 33–46 (1983). The first demonstration that long-term potentiation in the hippocampus is NMDAR-dependent.

    Article  CAS  Google Scholar 

  12. Mayer, M. L., Westbrook, G. L. & Guthrie, P. B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309, 261–263 (1984).

    Article  CAS  PubMed  Google Scholar 

  13. MacDermott, A. B., Mayer, M. L., Westbrook, G. L., Smith, S. J. & Barker, J. L. NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321, 519–522 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Nowak, L., Bregestovski, P., Ascher, P., Herbert, A. & Prochiantz, A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465 (1984). This study utilized the patch-clamp technique to provide the first evidence of a voltage-dependent Mg2+ block of the NMDA Ca2+ channel

    Article  CAS  PubMed  Google Scholar 

  15. Lester, R. A., Clements, J. D., Westbrook, G. L. & Jahr, C. E. Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature 346, 565–567 (1990).

    Article  CAS  PubMed  Google Scholar 

  16. 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). This paper was the first to show that NMDAR activity is needed for spatial learning and to draw parallels between NMDAR function, hippocampal synaptic plasticity and spatial learning.

    Article  CAS  PubMed  Google Scholar 

  17. Moriyoshi, K. et al. Molecular cloning and characterization of the rat NMDA receptor. Nature 354, 31–37 (1991). The first identification of a gene encoding a subunit of the NMDAR, which paved the way for much of the later genetic and structural work.

    Article  CAS  PubMed  Google Scholar 

  18. Dunah, A. W. et al. Biochemical studies of the structure and function of the N-methyl-D-aspartate subtype of glutamate receptors. Mol. Neurobiol. 19, 151–179 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Cull-Candy, S., Brickley, S. & Farrant, M. NMDA receptor subunits: diversity, development and disease. Curr. Opin. Neurobiol. 11, 327–335 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Li, Y., Erzurumulu, R., Chen, C., Jhaveri, S. & Tonegawa, S. Whisker-related neuronal patterns fail to develop in the trigeminal brainstem nuclei of NMDAR1 knockout mice. Cell 76, 427–437 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Forrest, D. et al. Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron 13, 325–338 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Amaral, D. G. & Witter, M. P. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Miles, R. & Wong, R. K. Excitatory synaptic interactions between CA3 neurones in the guinea-pig hippocampus. J. Physiol. (Lond.) 373, 397–418 (1986).

    Article  CAS  Google Scholar 

  24. MacVicar, B. A. & Dudek, F. E. Local synaptic circuits in rat hippocampus: interactions between pyramidal cells. Brain Res. 184, 220–223 (1980).

    Article  CAS  PubMed  Google Scholar 

  25. McClelland, J. L. & Goddard, N. H. Considerations arising from a complementary learning systems perspective on hippocampus and neocortex. Hippocampus 6, 654–665 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. McNaughton, B. L. & Morris, R. G. M. Hippocampal synaptic enhancement and information storage within a distributed memory system. Trends Neurosci. 10, 408–415 (1987).

    Article  Google Scholar 

  27. O'Reilly, R. C. & McClelland, J. L. Hippocampal conjunctive encoding, storage, and recall: avoiding a trade-off. Hippocampus 4, 661–682 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Marr, D. Simple memory: a theory for archicortex. Philos. Trans. R. Soc. London B 262, 23–81 (1971). A seminal work that laid the foundation of much of our current understanding of hippocampal computation. Marr's models include a discussion of partial-cue-based recall and experience-dependent modifications of synaptic strength.

    Article  CAS  Google Scholar 

  29. O'Reilly, R. C. & Rudy, J. W. Conjunctive representations in learning and memory: principles of cortical and hippocampal function. Psychol. Rev. 108, 311–345 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Morris, R. G. M. Spatial localization does not require the presence of local cues. Learn. Motiv. 12, 239–260 (1981).

    Article  Google Scholar 

  31. Davis, S., Butcher, S. P. & Morris, R. G. M. The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J. Neurosci. 12, 21–34 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Morris, R. G. M. Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J. Neurosci. 9, 3040–3057 (1989).

    Article  CAS  PubMed  Google Scholar 

  33. Riedel, G. et al. Reversible neural inactivation reveals hippocampal participation in several memory processes. Nature Neurosci. 2, 898–905 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Abraham, W. C. & Kairiss, E. W. Effects of the NMDA antagonist 2AP5 on complex spike discharge by hippocampal pyramidal cells. Neurosci. Lett. 89, 36–42 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Errington, M. L., Lynch, M. A. & Bliss, T. V. Long-term potentiation in the dentate gyrus: induction and increased glutamate release are blocked by D(–)aminophosphonovalerate. Neuroscience 20, 279–284 (1987).

    Article  CAS  PubMed  Google Scholar 

  36. Morris, R. G. M., Davis, S. & Butcher, S. P. Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Phil. Trans. R. Soc. Lond. B 329, 187–204 (1990).

    Article  CAS  Google Scholar 

  37. Hargreaves, E. L. & Cain, D. P. Hyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-D-aspartate non-competitive channel blocker MK801. Behav. Brain Res. 47, 23–33 (1992).

    Article  CAS  PubMed  Google Scholar 

  38. Sternberg, N., Hamilton, D. & Hoess, R. Bacteriophage P1 site-specific recombination. II. Recombination between loxP and the bacterial chromosome. J. Mol. Biol. 150, 487–507 (1981).

    Article  CAS  PubMed  Google Scholar 

  39. Hoess, R. H., Ziese, M. & Sternberg, N. P1 site-specific recombination: nucleotide sequence of the recombining sites. Proc. Natl Acad. Sci. USA 79, 3398–3402 (1982).

    Article  CAS  PubMed  Google Scholar 

  40. Tsien, J. Z., Huerta, P. T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996). This paper offered the first genetic demonstration of the effect of a brain-subregion-restricted NMDA receptor knockout on spatial memory.

    Article  CAS  PubMed  Google Scholar 

  41. McHugh, T. J., Blum, K. I., Tsien, J. Z., Tonegawa, S. & Wilson, M. A. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Cell 87, 1339–1349 (1996). This study was the first to show impaired coherent firing of CA1 place cells using genetically engineered NMDAR-knockout mice, demonstrating the powerful combination of conditional transgenic technology and multi-electrode recording.

    Article  CAS  PubMed  Google Scholar 

  42. Fukaya, M., Kato, A., Lovett, C., Tonegawa, S. & Watanabe, M. Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice. Proc. Natl Acad. Sci. USA 100, 4855–4860 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Huerta, P. T., Sun, L. D., Wilson, M. A. & Tonegawa, S. Formation of temporal memory requires NMDA receptors within CA1 pyramidal neurons. Neuron 25, 473–480 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Rondi-Reig, L., Libbey, M., Eichenbaum, H. & Tonegawa, S. CA1-specific N-methyl-D-aspartate receptor knockout mice are deficient in solving a nonspatial transverse patterning task. Proc. Natl Acad. Sci. USA 98, 3543–3548 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Rampon, C. et al. Enrichment induces structural changes and recovery from nonspatial-memory deficits in CA1-NMDAR1-knockout mice. Nature Neurosci. 3, 238–244 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Bannerman, D. M., Good, M. A., Butcher, S. P., Ramsay, M. & Morris, R. G. Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature 378, 182–186 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Saucier, D. & Cain, D. P. Spatial learning without NMDA receptor-dependent long-term potentiation. Nature 378, 186–189 (1995). References 46 and 47 provided strong evidence that NMDARs could be made dispensable for learning the water maze task if animals were pretrained on an identical spatial or even similar, non-spatial task. This was the first real evidence that the water maze task might involve several types of learning, some of which require NMDARs in the hippocampus and some of which do not.

    Article  CAS  PubMed  Google Scholar 

  48. Roesler, R. et al. Intrahippocampal infusion of the NMDA receptor antagonist AP5 impairs retention of an inhibitory avoidance task: protection from impairment by pretraining or preexposure to the task apparatus. Neurobiol. Learn. Mem. 69, 87–91 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Hoh, T., Beiko, J., Boon, F., Weiss, S. & Cain, D. P. Complex behavioral strategy and reversal learning in the watermaze without NMDA receptor-dependent long-term potentiation. J. Neurosci. 19, RC2(1–5) (1999).

    Article  Google Scholar 

  50. Steele, R. J. & Morris, R. G. M. Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5. Hippocampus 9, 118–136 (1999). This study showed that a delayed matching-to-place task in the water maze requires hippocampal NMDA receptors in rats, providing new insights into the involvement of the hippocampus in episodic-like memory.

    Article  CAS  PubMed  Google Scholar 

  51. Tulving, E. in Organization of Memory (eds Tulving, E. & Donaldson, W.) 381–403 (Academic, New York, 1972).

    Google Scholar 

  52. Tulving, E. Episodic memory: from mind to brain. Annu. Rev. Psychol. 53, 1–25 (2002).

    Article  PubMed  Google Scholar 

  53. Tulving, E. & Markowitsch, H. J. Episodic and declarative memory: role of the hippocampus. Hippocampus 8, 198–204 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Clayton, N. S. & Dickinson, A. Episodic-like memory during cache recovery by scrub jays. Nature 395, 272–274 (1998). Taking advantage of the natural caching behaviour of the scrub jay, these authors provide the strongest evidence for the existence of 'what, where and when (episodic-like) memory' in animals.

    Article  CAS  PubMed  Google Scholar 

  55. Clayton, N. S., Bussey, T. J. & Dickinson, A. Can animals recall the past and plan for the future? Nature Rev. Neurosci. 4, 685–691 (2003).

    Article  CAS  Google Scholar 

  56. Morris, R. G. M. Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative diseases. Philos. Trans. R. Soc. Lond. B 356, 1453–1465 (2001).

    Article  CAS  Google Scholar 

  57. Moser, M. B. & Moser, E. I. Pretraining and the function of hippocampal long-term potentiation. Neuron 26, 559–561 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Miles, R. & Traub, R. Excitatory synaptic interactions between CA3 neurons in the guinea-pig hippocampus. J. Physiol. (Lond.) 373, 397–418 (1986).

    Article  CAS  Google Scholar 

  59. MacVicar, B. & Dudek, F. Local synaptic circuits in rat hippocampus: interaction between pyramidal cells. Brain Res. 184, 220–223 (1980).

    Article  CAS  PubMed  Google Scholar 

  60. Harris, E. W. & Cotman, C. W. Long-term potentiation of guinea pig mossy fiber response is not blocked by N-methyl-D-aspartate antagonist. Neurosci. Lett. 70, 132–137 (1986).

    Article  CAS  PubMed  Google Scholar 

  61. Williams, S. & Johnston, D. Muscarinic depression of long-term potentiation in CA3 hippocampal neurons. Science 242, 84–87 (1988).

    Article  CAS  PubMed  Google Scholar 

  62. Zalutsky, R. A. & Nicoll, R. A. Comparison of two forms of long-term potentiation in single hippocampal neurons. Science 248, 1619–1624 (1990).

    Article  CAS  PubMed  Google Scholar 

  63. Berger, T. W. & Yeckel, M. F. in Long-Term Potentiation: A Debate of Current Issues (eds Baudry, M. & Davis, J. L.) 327–356 (MIT Press, Cambridge, Massachusetts, 1991).

    Google Scholar 

  64. Berzhanskaya, J., Urban, N. N. & Barrionuevo, G. Electrophysiological and pharmacological characterization of the direct perforant path input to hippocampal area CA3. J. Neurophysiol. 79, 2111–2118 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. McClelland, J. L., McNaughton, B. L., O'Reilly, R. C. & Nadel, L. Complementary roles of hippocampus and neocortex in learning and memory. Soc. Neurosci. Abstr. 18, 1216 (1992).

    Google Scholar 

  66. McClelland, J. L., McNaughton, B. L. & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: insights from the success and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457 (1995). The authors of references 65 and 66 formulated the theoretical basis of complementary learning systems of hippocampus and neocortex, which allows the brain to rapidly learn new on-line events without disrupting old off-line information, and to integrate these new events properly with previously stored experiences.

    Article  PubMed  Google Scholar 

  67. Lee, I. & Kesner, R. P. Differential contribution of NMDA receptors in hippocampal subregions to spatial working memory. Nature Neurosci. 5, 162–168 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Nakazawa, K. et al. Requirement for hippocampal CA3 NMDA receptors in acquisition and recall of associative memory. Science 297, 211–218 (2002). This study combines regionally restricted genetic modification with in vivo physiology and behaviour to provide strong evidence that NMDARs in region CA3 are required for memory recall by pattern completion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nakazawa, K. et al. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38, 305–315 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Vinogradova, O. S. in The Hippocampus (eds Isaacson, R. L. & Pribram, K. H.) 3–69 (Plenum, New York and London, 1975).

    Book  Google Scholar 

  71. McNaughton, B. L., Barnes, C. A., Meltzer, J. & Sutherland, R. J. Hippocampal granule cells are necessary for normal spatial learning but not for spatially-selective pyramidal cell discharge. Exp. Brain Res. 76, 485–496 (1989).

    Article  CAS  PubMed  Google Scholar 

  72. Brun, V. H. et al. Place cells and place recognition maintained by direct entorhinal-hippocampal circuitry. Science 296, 2243–2246 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Barnes, C. A., McNaughton, B. L., Mizumori, S. J., Leonard, B. W. & Lin, L. -H. Comparison of spatial and temporal characteristics of neuronal activity in sequential stages of hippocampal processing. Prog. Brain Res. 83, 287–300 (1990).

    Article  CAS  PubMed  Google Scholar 

  74. Frank, L. M., Brown, E. N. & Wilson, M. A. Trajectory encoding in the hippocampus and entorhinal cortex. Neuron 27, 169–178 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Quirk, G. J., Muller, R. U., Kubie, J. L. & Ranck, J. B. Jr. The positional firing properties of medial entorhinal neurons: description and comparison with hippocampal place cells. J. Neurosci. 12, 1945–1963 (1992).

    Article  CAS  PubMed  Google Scholar 

  76. Moser, E. I. & Moser, M. B. One-shot memory in hippocampal CA3 networks. Neuron 38, 147–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Day, M., Langston, R. & Morris, R. G. Glutamate-receptor-mediated encoding and retrieval of paired-associate learning. Nature 424, 205–209 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Ebbinghaus, H. Memory: A Contribution to Experimental Psychology (Dover, New York, 1885).

    Google Scholar 

  79. Müller, G. E. & Pilzecker, A. Experimentelle Beitrage zur Lehre vom Gedachtnis. Z. Psychol. Erganzungsband 1, 1–300 (1900).

    Google Scholar 

  80. McGaugh, J. L. Time-dependent processes in memory storage. Science 153, 1351–1358 (1966).

    Article  CAS  PubMed  Google Scholar 

  81. McGaugh, J. L. Memory: a century of consolidation. Science 287, 248–251 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Nader, K. Memory traces unbound. Trends Neurosci. 26, 65–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Squire, L. R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231 (1992).

    Article  CAS  PubMed  Google Scholar 

  84. Squire, L. R. & Alvarez, P. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr. Opin. Neurobiol. 5, 169–177 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Nadel, L. & Moscovitch, M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol. 7, 217–227 (1997).

    Article  CAS  PubMed  Google Scholar 

  86. Bontempi, B., Lauren-Demir, C., Destrade, C. & Jaffard, R. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671–675 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Davis, H. P. & Squire, L. R. Protein synthesis and memory: a review. Psych. Bull. 96, 518–559 (1984).

    Article  CAS  Google Scholar 

  88. DeZazzo, J. & Tully, T. Dissection of memory formation: from behavioral pharmacology to molecular genetics. Trends Neurosci. 18, 212–218 (1995).

    Article  CAS  PubMed  Google Scholar 

  89. Bailey, C. H., Bartsch, D. & Kandel, E. R. Toward a molecular definition of long-term memory storage. Proc. Natl Acad. Sci. USA 93, 13445–13452 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Nader, K., Schafem, G. E. & LeDoux, J. E. The labile nature of consolidation theory. Nature Rev. Neurosci. 1, 216–219 (2000).

    Article  CAS  Google Scholar 

  91. Abel, T. & Kandel, E. Positive and negative regulatory mechanisms that mediate long-term memory storage. Brain Res. Rev. 26, 360–378 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Adams, J. P. & Sweatt, J. D. Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu. Rev. Pharmacol. Toxicol. 42, 135–163 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Dudai, Y. Molecular bases of long-term memories: a question of persistence. Curr. Opin. Neurobiol. 12, 212–216 (2002).

    Article  Google Scholar 

  94. Bozon, B. et al. MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Philos. Trans. R. Soc. Lond. B 358, 805–814 (2003).

    Article  CAS  Google Scholar 

  95. Kang, H. et al. An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106, 771–783 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Kida, S. et al. CREB required for the stability of new and reactivated fear memories. Nature Neurosci. 5, 348–355 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Schafe, G. E., Nader, K., Blair, H. T. & LeDoux, J. E. Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci. 24, 540–546 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Taubenfeld, S. M., Milekic, M. H., Monti, B. & Alberini, C. M. The consolidation of new but not reactivated memory requires hippocampal C/EBPb. Nature Neurosci. 4, 813–818 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Abel, T. & Lattal, K. M. Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr. Opin. Neurobiol. 11, 180–187 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Izquierdo, I. & Medina, J. H. Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol. Learn. Mem. 68, 285–316 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Steward, O. & Schuman, E. M. Protein synthesis at synaptic sites on dendrites. Annu. Rev. Neurosci. 24, 299–325 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Kelleher, R. J., Govindarajan, A., Jung H. -Y., Kang, H. & Tonegawa, S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Wu, L. et al. CPEB-mediated cytoplasmic polyadenylation and the regulation of experience-dependent translation of α-CaMKII mRNA at synapses. Neuron 21, 1129–1139 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Heale, V. & Harley, C. MK-801 and AP5 impair acquisition, but not retention, of the Morris milk maze. Pharmacol. Biochem. Behav. 36, 145–149 (1990).

    Article  CAS  PubMed  Google Scholar 

  105. 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).

    Article  CAS  PubMed  Google Scholar 

  106. Packard, M. G. & Teather, L. A. Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentanoic acid. Behav. Neurosci. 111, 543–551 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Packard, M. G. & Teather, L. A. Posttraining injections of MK-801 produce a time-dependent impairment of memory in two water maze tasks. Neurobiol. Learn. Mem. 68, 42–50 (1997).

    Article  CAS  PubMed  Google Scholar 

  108. Shimizu, E., Tang, Y. P., Rampon, C. & Tsien, J. Z. NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290, 1170–1174 (2001).

    Article  Google Scholar 

  109. Gossen, M. & Bujard, H. Anhydrotetracycline, a novel effector for tetracycline controlled gene expression systems in eukaryotic cells. Nucleic Acids Res. 21, 4411–4412 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Stäubli, U., Thibault, O., DiLorenzo, M. & Lynch, G. Antagonism of NMDA receptors impairs acquisition but not retetion of olfactory memory. Behav. Neurosci. 103, 54–60 (1989).

    Article  PubMed  Google Scholar 

  111. Parada-Turska, J. & Turski, W. A. Excitatory amino acid antagonists and memory: effect of drugs acting at N-methyl-D-aspartate receptors in learning and memory tasks. Neuropharmacology 29, 1111–1116 (1990).

    Article  CAS  PubMed  Google Scholar 

  112. Venable, N. & Kelly, P. H. Effects of NMDA receptor antagonists on passive avoidance learning and retrieval in rats and mice. Psychopharmacology (Berl.) 100, 215–221 (1990).

    Article  CAS  Google Scholar 

  113. Szapiro, G. et al. Participation of hippocampal metabotropic glutamate receptors, protein kinase A and mitogen-activated protein kinases in memory retrieval. Neuroscience 99, 1–5 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Liang, K. C., Hon, W. & Davis, M. Pre- and posttraining infustion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task. Behav. Neurosci. 108, 241–253 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  116. Martin, S. J. & Morris, R. G. M. New life in an old idea: the synaptic plasticity and memory hypothesis revisited. Hippocampus 12, 609–636 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Chomsky, N. Syntactic Structures (Mouton, The Hague, 1957).

    Google Scholar 

  118. Gardner-Medwin, A. R. The recall of events through the learning of associations between their parts. Proc. R. Soc. Lond. B 194, 375–402 (1976).

    Article  CAS  PubMed  Google Scholar 

  119. Hopfield, J. J. Neural networks and physical systems with emergent collective computational abilities. Proc. Natl Acad. Sci. USA 79, 2554–2558 (1982).

    Article  CAS  PubMed  Google Scholar 

  120. Rolls, E. T. in The Computing Neuron (eds Durbin, R., Maill, C. & Mitchison, G.) 125–159 (Addison-Wesley, Wokingham, UK, 1989).

    Google Scholar 

  121. Willshaw, D. J. & Buckingham, J. T. An assessment of Marr's theory of the hippocampus as a temporary memory storage. Phil. Trans. R. Soc. Lond. B 329, 205–215 (1990).

    Article  CAS  Google Scholar 

  122. Hasselmo, M. E., Schnell, E. & Barkai, E. Dynamics of learning and recall at excitatory recurrent synapses and cholinergic modulation in rat hippocampal region CA3. J. Neurosci. 15, 5249–5262 (1995).

    Article  CAS  PubMed  Google Scholar 

  123. O'Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Clarendon, Oxford, 1978). This book uses both the animal and the human literature to outline a theory concerning the role of the hippocampus in spatial representation. The ideas outlined in this work have been the basis for countless experiments in the field and continue to generate important discussion.

    Google Scholar 

  124. Wilson, M. A. & McNaughton, B. L. Reactivation of hippocampal ensemble memories during sleep. Science 265, 676–679 (1994).

    Article  CAS  PubMed  Google Scholar 

  125. Wilson, M. A. & McNaughton, B. L. Dynamics of the hippocampal ensemble code for space. Science 261, 1055–1058 (1993). Utilizing multiple recording tetrodes, these authors monitored the simultaneous activity of more than one-hundred CA1 neurons as a rat explored the environment. This study was the first to look at hippocampal spatial activity on the level of a network and also the first to demonstrate the establishment of a spatial code in a novel environment.

    Article  CAS  PubMed  Google Scholar 

  126. Eichenbaum, H., Dudchenko, P., Wood, W., Shapiro, M. & Tanila, H. The hippocampus, memory, and place cells: is it spatial memory or a memory space? Neuron 23, 209–226 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. Lee, A. K. & Wilson, M. A. Memory of sequential experience in the hippocampus during slow wave sleep. Neuron 36, 1183–1194 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Louie, K. & Wilson, M. A. Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep. Neuron 29, 145–156 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Poucet, B., Save, E. & Lenck-Santini, P. P. Sensory and memory properties of hippocampal place cells. Rev. Neurosci. 11, 95–111 (2000).

    Article  CAS  PubMed  Google Scholar 

  130. Moser, E. I. & Paulsen, O. New excitement in cognitive space: between place cells and spatial memory. Curr. Opin. Neurobiol. 11, 745–751 (2001). The authors reviewed recent evidence connecting hippocampal place cell activity with its mnemonic function.

    Article  CAS  PubMed  Google Scholar 

  131. Skaggs, W. E. & McNaughton, B. L. Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience. Science 271, 1870–1873 (1996).

    Article  CAS  PubMed  Google Scholar 

  132. Kudrimoti, H., Barnes, C. A. & McNaughton, B. L. Reactivation of hippocampal cell assemblies: effects of behavioral state, experience, and EEG dynamics. J. Neurosci. 19, 4090–4101 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Nadasdy, Z., Hirase, H., Czurko, A., Csicsvari, J. & Buzsaki, G. Replay and time compression of recurring spike sequences in the hippocampus. J. Neurosci. 19, 9497–9507 (1999).

    Article  CAS  PubMed  Google Scholar 

  134. Muller, R. U. & Kubie, J. L. The effects of changes in the environment on the spatial firing of hippocampal complex-spike cells. J. Neurosci. 7, 1951–1968 (1987).

    Article  CAS  PubMed  Google Scholar 

  135. O'Keefe, J. & Conway, D. H. Hippocampal place units in the freely moving rat: why they fire where they fire. Exp. Brain. Res. 31, 573–590 (1978).

    Article  CAS  PubMed  Google Scholar 

  136. O'Keefe, J. & Speakman, A. Single unit activity in the rat hippocampus during a spatial memory task. Exp. Brain Res. 68, 1–27 (1987).

    Article  CAS  PubMed  Google Scholar 

  137. Pico, R. M., Gerbrandt, L. K., Pondel, M. & Ivy, G. During stepwise cue deletion, rat place behaviors correlate with place unit responses. Brain Res. 330, 369–372 (1985).

    Article  CAS  PubMed  Google Scholar 

  138. Mehta, M. R., Barnes, C. A. & McNaughton, B. L. Experience-dependent, asymmetric expansion of hippocampal place fields. Proc. Natl Acad. Sci. USA 94, 8918–8921 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Mehta, M. R., Quirk, M. C. & Wilson, M. A. Experience-dependent asymmetric shape of hippocampal receptive fields. Neuron 25, 707–715 (2000).

    Article  CAS  PubMed  Google Scholar 

  140. Kentros, C. et al. Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science 280, 2121–2126 (1998). Combining pharmacology and in vivo recording, the authors show that acute blockade of the NMDAR during the exploration of a novel environment impairs the long-term stability of the newly encoded place fields.

    Article  CAS  PubMed  Google Scholar 

  141. Ekstrom, A. D., Meltzer, J., McNaughton, B. L. & Barnes, C. A. NMDA receptor antagonism blocks experience-dependent expansion of hippcampal 'place fields'. Neuron 31, 631–638 (2001). The authors demonstrated, using the NMDAR antagonist CPP, that experience-dependent asymmetric place field expansion in hippocampal CA1 is NR-dependent, but phase precession on the theta wave is not.

    Article  CAS  PubMed  Google Scholar 

  142. Rotenberg, A., Mayford, M., Hawkins, R. D., Kandel, E. R. & Muller, R. U. Mice expressing activated CaMKII lack low frequency LTP and do not form stable place cells in the CA1 region of the hippocampus. Cell 87, 1351–1361 (1996).

    Article  CAS  PubMed  Google Scholar 

  143. Rotenberg, A., Abel, T., Hawkins, R. D., Kandel, E. R. & Muller, R. U. Parallel instabilities of long-term potentiation, place cells, and learning caused by decreased protein kinase A activity. J. Neurosci. 20, 8096–8102 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Yan, J. et al. Place-cell impairment in glutamate receptor 2 mutant mice. J. Neurosci. 22, RC204 (2002).

    Article  PubMed  Google Scholar 

  145. Cho, Y. H., Giese, K. P., Tanila, H., Silva, A. J. & Eichenbaum, H. Abnormal hippocampal spatial representations in aCaMKIIT286A and CREBα/− mice. Science 279, 867–869 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Muller, R. U., Bostock, E., Taube, J. S. & Kubie, J. L. On the directional firing properties of hippocampal place cells. J. Neurosci. 14, 7235–7251 (1994).

    Article  CAS  PubMed  Google Scholar 

  147. Anderson, M. I. & Jeffery, K. J. Heterogeneous modulation of place cell firing by changes in context. J. Neurosci. 23, 8827–8835 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Wood, E. R., Dudchenko, P. A., Robitsek, R. J. & Eichenbaum, H. Hippocampal neurons encode information about different types of memory episodes occurring in the same location. Neuron 27, 623–633 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Young, B. J., Fox, G. D. & Eichenbaum, H. Correlates of hippocampal complex-spike cell activity in rats performing a nonspatial radial maze task. J. Neurosci. 14, 6553–6563 (1994).

    Article  CAS  PubMed  Google Scholar 

  150. Hollup, S. A., Molden, S., Donnett, J. G., Moser, M. B. & Moser, E. I. Accumulation of hippocampal place fields at the goal location in an annular watermaze task. J. Neurosci. 21, 1635–1644 (2001).

    Article  CAS  PubMed  Google Scholar 

  151. Fyhn, M., Molden, S., Hollup, S., Moser, M. -B. & Moser, E. I. Hippocampal neurons responding to first-time dislocation of a target object. Neuron 35, 555–566 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. Rolls, E. T. A theory of hippocampal function in memory. Hippocampus 6, 601–620 (1996).

    Article  CAS  PubMed  Google Scholar 

  153. O'Keefe, J. Hippocampus, theta, and spatial memory. Curr. Opin. Neurobiol. 3, 917–924 (1993).

    Article  CAS  PubMed  Google Scholar 

  154. O'Keefe, J. A review of the hippocampal place cells. Prog. Neurobiol. 13, 419–349 (1979).

    Article  CAS  PubMed  Google Scholar 

  155. Muller, R. U., Stead, M. & Pach, J. The hippocampus as a cognitive graph. J. Gen. Physiol. 107, 663–694 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Best, P. J., White, A. M. & Minai, A. Spatial processing in the brain: the activity of hippocampal place cells. Annu. Rev. Neurosci. 24, 459–486 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Thompson, L. T. & Best, P. J. Long-term stability of the place-field activity of single units recorded from the dorsal hippocampus of freely behaving rats. Brain Res. 509, 299–308 (1990).

    Article  CAS  PubMed  Google Scholar 

  158. Muller, R. A quarter of a century of place cells. Neuron 17, 813–822 (1996).

    Article  CAS  PubMed  Google Scholar 

  159. Redish, A. D. et al. Independence of firing correlates of anatomically proximate hippocampal pyramidal cells. J. Neurosci. 21, RC134 (2001).

    Article  CAS  PubMed  Google Scholar 

  160. Branda, C. S. & Dymecki, S. M. Talking about a revolution: The impact of site-specific recombinases on genetic analyses in mice. Dev. Cell 6, 7–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Morozov, A., Kellendonk, C., Simpson, E. & Tronche, F. Using conditional mutagenesis to study the brain. Biol. Psychiatry 54, 1125–1133 (2003).

    Article  CAS  PubMed  Google Scholar 

  162. Grant, S. G. N. et al. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258, 1903–1909 (1992).

    Article  CAS  PubMed  Google Scholar 

  163. Blendy, J. A., Kaestner, K. H., Schmid, W., Gass, P. & Schutz, G. Targeting of the CREB gene leads to up-regulation of a novel CREB mRNA isoform. EMBO J. 15, 1098–1106 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Hummler, E. et al. Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc. Natl Acad. Sci. USA 91, 5647–5651 (1994).

    Article  CAS  PubMed  Google Scholar 

  165. Mills, A. A. Changing colors in mice: an inducible system that delivers. Genes Dev. 15, 1461–1467 (2001).

    Article  CAS  PubMed  Google Scholar 

  166. Schonig, K. & Bujard, H. Generating conditional mouse mutants via tetracycline-controlled gene expression. Methods Mol. Biol. 209, 69–104 (2003).

    PubMed  Google Scholar 

  167. Gross, C. et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396–400 (2002).

    Article  CAS  PubMed  Google Scholar 

  168. Chen, J. et al. Transgenic animals with inducible, targeted gene expression in brain. Mol. Pharmacol. 54, 495–503 (1998).

    Article  CAS  PubMed  Google Scholar 

  169. Mayford, M. et al. Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678–1683 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by an individual NIH grant to S.T. and an NIH Silvio O. Conte Center grant to S.T. and M.A.W., and by grants from the Howard Hughes Medical Institute to S.T. and from the RIKEN-MIT Neuroscience Research Center to S.T. and M.A.W.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Susumu Tonegawa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Nakazawa's homepage

Tonegawa's homepage

Wilson's homepage

Glossary

FEAR CONDITIONING

A form of Pavlovian (classical) conditioning in which the animal learns that an innocuous stimulus (for example, an auditory tone — the conditioned stimulus or CS), reliably predicts the occurrence of a noxious stimulus (for example, foot shock — the unconditioned stimulus or US) following their repeated paired presentation. As a result of this procedure, presentation of the CS alone elicits conditioned fear responses previously associated with the noxious stimulus only.

TRANSVERSE PATTERN LEARNING

A task in which animals must encode overlapping relationships between cues. A typical stimulus set is A+B−; B+C−; C+A−, where + signifies which cue is rewarded in each configuration.

STEP-DOWN INHIBITORY AVOIDANCE TASK

A form of conditioning in which a rat is placed on a platform and receives a shock when it steps off the platform. Memory for the shock is measured as an increased latency to step off the platform on subsequent trials.

PAIRED-ASSOCIATE TASK

A task that involves the arbitrary association of two stimuli (such as word pairs in humans, or a place and an odour or food item in animals). After exposure to the pair, the subject is presented with one stimulus and tested for recall of the second. It can be used to test declarative memory in humans, or 'episodic-like' memory in animals.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakazawa, K., McHugh, T., Wilson, M. et al. NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci 5, 361–372 (2004). https://doi.org/10.1038/nrn1385

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1385

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing