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Protein phosphatase 1 is a molecular constraint on learning and memory

Abstract

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.

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Acknowledgements

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). https://doi.org/10.1038/nature00928

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