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Protein phosphatase 1 is a molecular constraint on learning and memory


Repetition in learning is a prerequisite for the formation of accurate and long-lasting memory. Practice is most effective when widely distributed over time, rather than when closely spaced or massed. But even after efficient learning, most memories dissipate with time unless frequently used1,2. The molecular mechanisms of these time-dependent constraints on learning and memory are unknown. Here we show that protein phosphatase 1 (PP1) determines the efficacy of learning and memory by limiting acquisition and favouring memory decline. When PP1 is genetically inhibited during learning, short intervals between training episodes are sufficient for optimal performance. The enhanced learning correlates with increased phosphorylation of cyclic AMP-dependent response element binding (CREB) protein, of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and of the GluR1 subunit of the AMPA receptor; it also correlates with CREB-dependent gene expression that, in control mice, occurs only with widely distributed training. Inhibition of PP1 prolongs memory when induced after learning, suggesting that PP1 also promotes forgetting. This property may account for ageing-related cognitive decay, as old mutant animals had preserved memory. Our findings emphasize the physiological importance of PP1 as a suppressor of learning and memory, and as a potential mediator of cognitive decline during ageing.

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Figure 1: Distributed training improves performance in the object recognition task.
Figure 2: Genetic or training-dependent inhibition of PP1.
Figure 3: Enhanced CREB activity and phosphorylation.
Figure 4: Improved spatial learning and memory in I-1* mutant mice.


  1. Spear, N. E. The Processing of Memories: Forgetting and Retention (Erlbaum, Hillsdale, New Jersey, 1978)

    Google Scholar 

  2. Spear, N. E. & Riccio, D. C. Memory: Phenomena and Principles (Allyn and Bacon, Needham Heights, Massachusetts, 1994)

    Google Scholar 

  3. Sara, S. J. Retrieval and reconsolidation: toward a neurobiology of remembering. Learn. Mem. 7, 73–84 (2000)

    CAS  Article  Google Scholar 

  4. Abel, T., Martin, K. C., Bartsch, D. & Kandel, E. R. Memory suppressor genes: inhibitory constraints on the storage of long-term memory. Science 279, 338–341 (1998)

    ADS  CAS  Article  Google Scholar 

  5. Sweatt, J. D. Memory mechanisms: the yin and yang of protein phosphorylation. Curr. Biol. 11, 391–394 (2001)

    Article  Google Scholar 

  6. 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)

    CAS  Article  Google Scholar 

  7. Mansuy, I. M. et al. Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron 21, 257–265 (1998)

    CAS  Article  Google Scholar 

  8. 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)

    CAS  Article  Google Scholar 

  9. Lisman, J. E. A mechanism for the Hebb and anti-Hebb processes underlying learning and memory. Proc. Natl Acad. Sci. USA 86, 9574–9578 (1989)

    ADS  CAS  Article  Google Scholar 

  10. Morishita, W. et al. Regulation of synaptic strength by protein phosphatase 1. Neuron 32, 1133–1148 (2001)

    CAS  Article  Google Scholar 

  11. Save, E., Poucet, B., Foreman, N. & Buhot, M. C. Object exploration and reactions to spatial and nonspatial changes in hooded rats following damage to parietal cortex or hippocampal formation. Behav. Neurosci. 106, 447–456 (1992)

    CAS  Article  Google Scholar 

  12. Alberts, A. S., Montminy, M., Shenolikar, S. & Feramisco, J. R. Expression of a peptide inhibitor of protein phosphatase 1 increases phosphorylation and activity of CREB in NIH 3T3 fibroblasts. Mol. Cell Biol. 14, 4398–4407 (1994)

    CAS  Article  Google Scholar 

  13. Huang, F. L. & Glinsmann, W. H. Separation and characterization of two phosphorylase phosphatase inhibitors from rabbit skeletal muscle. Eur. J. Biochem. 70, 419–426 (1976)

    CAS  Article  Google Scholar 

  14. Gossen, M. et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  16. Silva, A. J., Kogan, J. H., Frankland, P. W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998)

    CAS  Article  Google Scholar 

  17. Hagiwara, M. et al. Transcriptional attenuation following cAMP induction requires PP1-mediated dephosphorylation of CREB. Cell 70, 105–113 (1992)

    CAS  Article  Google Scholar 

  18. Impey, S. et al. Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16, 973–982 (1996)

    CAS  Article  Google Scholar 

  19. Gonzalez, G. A. & Montminy, M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59, 675–680 (1989)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  21. 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)

    CAS  Article  Google Scholar 

  22. Lisman, J., Malenka, R. C., Nicoll, R. A. & Malinow, R. Learning mechanisms: the case for CaMKII. Science 276, 2001–2002 (1997)

    CAS  Article  Google Scholar 

  23. Lisman, J. E. & Zhabotinsky, A. M. A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly. Neuron 31, 191–201 (2001)

    CAS  Article  Google Scholar 

  24. Blitzer, R. D. et al. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280, 1940–1942 (1998)

    ADS  CAS  Article  Google Scholar 

  25. Gallagher, M. & Rapp, P. R. The use of animal models to study the effects of aging on cognition. Annu. Rev. Psychol. 48, 339–370 (1997)

    CAS  Article  Google Scholar 

  26. Foster, T. C., Sharrow, K. M., Masse, J. R., Norris, C. M. & Kumar, A. Calcineurin links Ca2+ dysregulation with brain aging. J. Neurosci. 21, 4066–4073 (2001)

    CAS  Article  Google Scholar 

  27. Norris, C. M., Halpain, S. & Foster, T. C. Alterations in the balance of protein kinase/phosphatase activities parallel reduced synaptic strength during aging. J. Neurophysiol. 80, 1567–1570 (1998)

    CAS  Article  Google Scholar 

  28. Villarreal, D. M., Do, V., Haddad, E. & Derrick, B. E. NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay. Nature Neurosci. 5, 48–52 (2002)

    CAS  Article  Google Scholar 

  29. Connor, J. H., Quan, H., Oliver, C. & Shenolikar, S. Inhibitor-1, a regulator of protein phosphatase 1 function. Methods Mol. Biol. 93, 41–58 (1998)

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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We thank S. Shenolikar for the I-1 reagents; I. Weiss, G. Hédou, F. Dey, A. Hirschy and M. Nemir for technical help; V. Taylor for assistance with animals; A. Jongen-Relo for help with stereology; D. Benke for help with membrane-enriched preparations; and T. Bliss for reading the manuscript. This work was supported by the Swiss Federal Institute of Technology, the Swiss National Science Foundation and the National Center of Competence in Research.

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Correspondence to Isabelle M. Mansuy.

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Genoux, D., Haditsch, U., Knobloch, M. et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418, 970–975 (2002).

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