Article | Published:

Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice

Nature Neurosciencevolume 3pages238244 (2000) | Download Citation

Subjects

Abstract

We produced CA1-specific NMDA receptor 1 subunit-knockout (CA1-KO) mice to determine the NMDA receptor dependence of nonspatial memory formation and of experience-induced structural plasticity in the CA1 region. CA1-KO mice were profoundly impaired in object recognition, olfactory discrimination and contextual fear memories. Surprisingly, these deficits could be rescued by enriching experience. Using stereological electron microscopy, we found that enrichment induced an increase of the synapse density in the CA1 region in knockouts as well as control littermates. Therefore, our data indicate that CA1 NMDA receptor activity is critical in hippocampus-dependent nonspatial memory, but is not essential for experience-induced synaptic structural changes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Rosene, D. L. & Van Hoesen, G. W. in Cerebral Cortex Vol. 6: Further Aspects of Cortical Function, Including Hippocampus (eds. Jones, E. G. & Petes, A.) 345–447 (Plenum, New York, 1987).

  2. 2

    Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesion. J. Neurol. Neurosurg. Psychiatry 20, 11–12 ( 1957).

  3. 3

    Zola-Morgan, S., Squire, L. R. & Amaral, D. G. Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J. Neurosci. 6, 2950– 2967 (1986).

  4. 4

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

  5. 5

    Mumby, D. G. et al. Ischemia-induced object-recognition deficits in rats are attenuated by hippocampal ablation before or soon after ischemia. Behav. Neurosci. 110, 266–281 ( 1996).

  6. 6

    Wood, E. R., Dudchenko, P. A. & Eichenbaum, H. The global record of memory in hippocampal neuronal activity. Nature 397, 613– 616 (1999).

  7. 7

    Moriyoshi, K. et al. Molecular cloning and characterization of the rat NMDA receptor . Nature 354, 31–37 (1991).

  8. 8

    Nicoll, R. A. & Malenka, R. C. Expression mechanisms underlying NMDA receptor-dependent long-term potentiation. Ann. NY Acad. Sci. 868, 515–525 ( 1999).

  9. 9

    Bear, M. F. & Malenka, R. C. Synaptic plasticity: LTP and LTD. Curr. Opin. Neurobiol. 4, 389– 399 (1994).

  10. 10

    Tang, Y.-P et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 ( 1999).

  11. 11

    Tsien, J. Z. et al. Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87, 1317–1326 (1996).

  12. 12

    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).

  13. 13

    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).

  14. 14

    Woolf, N. J. A structural basis for memory storage in mammals. Prog. Neurobiol. 55, 59–77 ( 1998).

  15. 15

    Bailey, C. H. & Kandel, E. R. Structural changes accompanying memory storage. Annu. Rev. Physiol. 55, 397–426 (1993).

  16. 16

    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).

  17. 17

    Goodman, C. S. & Shatz, C. J. Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell 72, Suppl. 77–98 (1993).

  18. 18

    Li, Y., Erzurumlu, R. S., 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).

  19. 19

    Kirov, S. A. & Harris, K. M. Dendrites are more spiny on mature hippocampal neurons when synapses are inactivated. Nat. Neurosci. 10, 878–883 ( 1999).

  20. 20

    Sorra, K. E. & Harris, K. M. Stability in synapse number and size at 2 hr after long-term potentiation in hippocampal area CA1. J. Neurosci. 18, 658–671 (1998).

  21. 21

    Mansuy, I. M., Mayford, M., Jacob, B., Kandel, E. R. & Bach, M. E. Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell 92, 39–49 ( 1998).

  22. 22

    Kogan, J. H. et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 7, 1– 11 (1996).

  23. 23

    Strupp, B. J. & Levitsky, D. A. Social transmission of food preferences in adult hooded rats (Rattus norvegicus). J. Comp. Psychol. 98, 257–266 (1984).

  24. 24

    Bunsey, M. & Eichenbaum, H. Selective damage to the hippocampal region blocks long-term retention of a natural and nonspatial stimulus-stimulus association. Hippocampus 5, 546– 556 (1995).

  25. 25

    Phillips, R. G. & LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning . Behav. Neurosci. 106, 274– 285 (1992).

  26. 26

    Kempermann, G., Kuhn, G. H. & Gage, F. H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493– 495 (1997).

  27. 27

    Dalrymple-Alford, J. C. & Benton, D. Preoperative differential housing and dorsal hippocampal lesions in rats. Behav. Neurosci. 98, 23–34 ( 1984).

  28. 28

    Rosenzweig, M. R. Environmental complexity, cerebral change, and behavior. Am. Psychol. 21, 321–332 ( 1966).

  29. 29

    Diamond, M. C. Enriching Heredity: The Impact of the Environment on the Anatomy of the Brain (Free Press, New York, 1988).

  30. 30

    Fiala, B. A., Joyce, J. N. & Greenough, W. T. Environmental complexity modulates growth of granule cell dendrites in developing but not adult hippocampus of rats. Exp. Neurol. 59, 372–383 (1978).

  31. 31

    Greenough, W. T., Withers, G. S. & Wallace, C. S. in The Biology of Memory (eds. Squire, L. R. & Lindenbaum, E.) 159–185 (Schattauer, Stuttgart, 1990).

  32. 32

    Gabbott, P. L & Somogyi, J. The “single” Golgi impregnation procedure: methodological description. J. Neurosci. Methods 11, 221–230 (1984).

  33. 33

    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).

  34. 34

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

  35. 35

    DeGroot, D. M. G. & Bierman, E. P. B. A critical evaluation of methods for estimating the numerical density of synapses. J. Neurosci. Methods 18, 79–101 (1986).

  36. 36

    Gray, E. G. Axosomatic and axodendritic synapses of the cerebral cortex: An electron microscopic study. J. Anat. 83, 420– 433 (1959).

  37. 37

    Nicoll, R. A. & Malenka, R. C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377, 115–118 (1995).

  38. 38

    Stevens, C. F. & Sullivan, J. Synaptic plasticity . Curr. Biol. 8, R151–153 (1998).

  39. 39

    Woolley, C. S., Gould, E., Frankfurt, M. & McEwen, B. S. Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons . J. Neurosci. 10, 4035– 4039 (1990).

  40. 40

    Franklin, K. B. J. & Paxinos, G. The mouse brain in stereotaxic coordinates. (Academic, San Diego, 1997 ).

  41. 41

    Gundersen, H. J. G. Notes on the estimation of the numerical density of arbitrary profiles: the edge effect. J. Microsc. 111, 219– 223 (1977).

Download references

Acknowledgements

We thank E. Gould for help with stereology and statistics and reading the manuscript, and P. Tanapat for technical advice concerning the Golgi method. This work was supported in part by a postdoctoral fellowship from Fondation pour la Recherche Medicale to C.R. and by grants from Princeton University, Beckman Foundation and NIH to J.Z.T.

Author information

Author notes

  1. Claire Rampon and Ya-Ping Tang: The first two authors contributed equally to this work.

Affiliations

  1. Department of Molecular Biology, Princeton University, Washington Road, Princeton, 08540-1014, New Jersey, USA

    • Claire Rampon
    • , Ya-Ping Tang
    • , Joe Goodhouse
    • , Eiji Shimizu
    • , Maureen Kyin
    •  & Joe Z. Tsien

Authors

  1. Search for Claire Rampon in:

  2. Search for Ya-Ping Tang in:

  3. Search for Joe Goodhouse in:

  4. Search for Eiji Shimizu in:

  5. Search for Maureen Kyin in:

  6. Search for Joe Z. Tsien in:

Corresponding author

Correspondence to Joe Z. Tsien.

Supplementary information

About this article

Publication history

Received

Accepted

Issue Date

DOI

https://doi.org/10.1038/72945

Further reading