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 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 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.

[1]  F. Huang,et al.  Separation and characterization of two phosphorylase phosphatase inhibitors from rabbit skeletal muscle. , 1976, European journal of biochemistry.

[2]  Norman E. Spear,et al.  The processing of memories : forgetting and retention , 1980 .

[3]  H. Spero,et al.  PHAGOTROPHIC FEEDING AND ITS IMPORTANCE TO THE LIFE CYCLE OF THE HOLOZOIC DINOFLAGELLATE, GYMNODINIUM FUNGIFORME 1 , 1981 .

[4]  R. Morris,et al.  Place navigation impaired in rats with hippocampal lesions , 1982, Nature.

[5]  L. Squire,et al.  Protein synthesis and memory: a review. , 1984, Psychological bulletin.

[6]  J. Lisman,et al.  A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Montminy,et al.  Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133 , 1989, Cell.

[8]  M. Hagiwara,et al.  Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB , 1992, Cell.

[9]  Edward J. Noga,et al.  New 'phantom' dinoflagellate is the causative agent of major estuarine fish kills , 1992, Nature.

[10]  E Save,et al.  Object exploration and reactions to spatial and nonspatial changes in hooded rats following damage to parietal cortex or hippocampal formation. , 1992, Behavioral neuroscience.

[11]  E. Schnepf,et al.  Nutritional strategies in dinoflagellates: A review with emphasis on cell biological aspects. , 1992, European journal of protistology.

[12]  J R Feramisco,et al.  Expression of a peptide inhibitor of protein phosphatase 1 increases phosphorylation and activity of CREB in NIH 3T3 fibroblasts , 1994, Molecular and cellular biology.

[13]  Norman E. Spear,et al.  Memory: Phenomena and Principles , 1994 .

[14]  J. Burkholder,et al.  Fish kills linked to a toxic ambush-predator dinoflagellate: distribution and environmental conditions , 1995 .

[15]  M. Gossen,et al.  Transcriptional activation by tetracyclines in mammalian cells. , 1995, Science.

[16]  J. Burkholder,et al.  Insidious effects of a toxic estuarine dinoflagellate on fish survival and human health. , 1995, Journal of toxicology and environmental health.

[17]  E. Villacres,et al.  Induction of CRE-Mediated Gene Expression by Stimuli That Generate Long-Lasting LTP in Area CA1 of the Hippocampus , 1996, Neuron.

[18]  E. Kandel,et al.  Control of Memory Formation Through Regulated Expression of a CaMKII Transgene , 1996, Science.

[19]  J. Burkholder,et al.  Novel toxic dinoflagellate causes epidemic disease in estuarine fish , 1996 .

[20]  R. Colbran,et al.  Differential Inactivation of Postsynaptic Density‐Associated and Soluble Ca2+/Calmodulin‐Dependent Protein Kinase II by Protein Phosphatases 1 and 2A , 1997, Journal of neurochemistry.

[21]  Roberto Malinow,et al.  Learning Mechanisms: The Case for CaM-KII , 1997, Science.

[22]  M. Gallagher,et al.  The use of animal models to study the effects of aging on cognition. , 1997, Annual review of psychology.

[23]  E. Kandel,et al.  Memory suppressor genes: inhibitory constraints on the storage of long-term memory. , 1998, Science.

[24]  Alcino J. Silva,et al.  CREB and memory. , 1998, Annual review of neuroscience.

[25]  S. Shenolikar,et al.  Inhibitor-1, a regulator of protein phosphatase 1 function. , 1998, Methods in molecular biology.

[26]  S. Shenolikar,et al.  Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. , 1998, Science.

[27]  E. Kandel,et al.  Inducible and Reversible Gene Expression with the rtTA System for the Study of Memory , 1998, Neuron.

[28]  Eric R Kandel,et al.  Restricted and Regulated Overexpression Reveals Calcineurin as a Key Component in the Transition from Short-Term to Long-Term Memory , 1998, Cell.

[29]  T. Foster,et al.  Alterations in the balance of protein kinase/phosphatase activities parallel reduced synaptic strength during aging. , 1998, Journal of neurophysiology.

[30]  V. Blazer,et al.  Aphanomyces as a Cause of Ulcerative Skin Lesions of Menhaden from Chesapeake Bay Tributaries , 1999 .

[31]  S. Sara.  Retrieval and reconsolidation: toward a neurobiology of remembering. , 2000, Learning & memory.

[32]  E. Silbergeld,et al.  The N-methyl-D-aspartate neurotransmitter receptor is a mammalian brain target for the dinoflagellate Pfiesteria piscicida toxin. , 2000, Toxicology and applied pharmacology.

[33]  Eric R. Kandel,et al.  Inducible and Reversible Enhancement of Learning, Memory, and Long-Term Potentiation by Genetic Inhibition of Calcineurin , 2001, Cell.

[34]  J. Burkholder,et al.  A second species of ichthyotoxic Pfiesteria (Dinamoebales, Dinophyceae) , 2001 .

[35]  Wade Morishita,et al.  Regulation of Synaptic Strength by Protein Phosphatase 1 , 2001, Neuron.

[36]  T. Foster,et al.  Calcineurin Links Ca2+ Dysregulation with Brain Aging , 2001, The Journal of Neuroscience.

[37]  K. Reece,et al.  Skin ulcers in estuarine fishes: a comparative pathological evaluation of wild and laboratory-exposed fish. , 2001, Environmental health perspectives.

[38]  J. Burkholder,et al.  Overview and present status of the toxic Pfiesteria complex (Dinophyceae) , 2001 .

[39]  J. Sweatt,et al.  Memory mechanisms: The yin and yang of protein phosphorylation , 2001, Current Biology.

[40]  J. Lisman,et al.  A Model of Synaptic Memory A CaMKII/PP1 Switch that Potentiates Transmission by Organizing an AMPA Receptor Anchoring Assembly , 2001, Neuron.

[41]  J. Burkholder,et al.  The standardized fish bioassay procedure for detecting and culturing actively toxic Pfiesteria, used by two reference laboratories for atlantic and gulf coast states. , 2001, Environmental health perspectives.

[42]  V. Blazer,et al.  Aphanomyces invadans in Atlantic Menhaden along the East Coast of the United States , 2002 .

[43]  V. Blazer,et al.  Induction of Skin Ulcers in Atlantic Menhaden by Injection and Aqueous Exposure to the Zoospores of Aphanomyces invadans , 2002 .

[44]  B. Derrick,et al.  NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay , 2002, Nature Neuroscience.