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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 used. 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 Ca(2+)/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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“One study in mice61 found marked phosphorylation and activation of CREB in the hippocampus and the cortex when object recognition trials were separated by an interval of 15 minutes but not by an interval of 5 minutes.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [61]
In the citing paper
“Protein phosphatase 1 (PP1) appeared to be necessary for this spacing effect, because PP1 inhibition allowed the shorter interval to activate CREB.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [61]
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Metadata
- Authors
- Genoux, D., Haditsch, U., Knobloch, M., Michalon, A., Storm, D., & Mansuy, I. M.
- Affiliations
- ETH Zurich (CH)
- University of Washington (US)
- Corresponding author
- Mansuy, Isabelle M.
- Venue
- Nature
- Published
- 2002-08
- Volume
- 418
- Issue
- 6901
- Pages
- 970-975
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1992020799
- Cited by
- 472
- References
- 30
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 18 · 2023: 7 · 2022: 16 · 2021: 17 · 2020: 15 · 2019: 16 · 2018: 15 · 2017: 10 · 2016: 22 · 2015: 21 · 2014: 24 · 2013: 26 · 2012: 21
- FWCI
- 15.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- protein phosphatase 1, learning and memory, forgetting, memory consolidation, CREB phosphorylation, CaMKII, GluR1, AMPA receptors, cognitive decline, protein dephosphorylation
- MeSH terms
- Aging, Animals, Cognition, Discrimination, Psychological, Gene Expression Regulation, Hippocampus, Learning, Memory, Mice, Transgenic, Mutation, Phosphoprotein Phosphatases, Phosphorylation, Space Perception, Time Factors, Cyclic AMP Response Element-Binding Protein, Calcium-Calmodulin-Dependent Protein Kinases, Receptors, AMPA, Protein Subunits, Mice, Protein Phosphatase 1, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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