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How does PKMζ maintain long-term memory?

Nature Reviews Neuroscience volume 12, pages 9–15 (2011)Cite this article

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Abstract

Most of the molecular mechanisms contributing to long-term memory have been found to consolidate information within a brief time window after learning, but not to maintain information during memory storage. However, with the discovery that synaptic long-term potentiation is maintained by the persistently active protein kinase, protein kinase Mζ (PKMζ), a possible mechanism of memory storage has been identified. Recent research shows how PKMζ might perpetuate information both at synapses and during long-term memory.

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Figure 1: PKMζ formation in LTP.
Figure 2: Mechanism of synaptic potentiation by PKMζ in LTP maintenance.
Figure 3: Model of PKMζ synaptic autotagging in memory maintenance.

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References

  1. Kandel, E. R. & Schwartz, J. H. Molecular biology of learning: modulation of transmitter release. Science 218, 433–443 (1982).

    Article  CAS  PubMed  Google Scholar 

  2. Dudai, Y. Neurogenetic dissection of learning and short-term memory in Drosophila. Annu. Rev. Neurosci. 11, 537–563 (1988).

    Article  CAS  PubMed  Google Scholar 

  3. Sanes, J. R. & Lichtman, J. W. Can molecules explain long-term potentiation? Nature Neurosci. 2, 597–604 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Nader, K., Schafe, G. E. & LeDoux, J. E. The labile nature of consolidation theory. Nature Rev. Neurosci. 1, 216–219 (2000).

    Article  CAS  Google Scholar 

  5. Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

    CAS  PubMed  Google Scholar 

  6. Hernandez, A. I. et al. Protein kinase Mζ synthesis from a brain mRNA encoding an independent protein kinase Cζ catalytic domain. Implications for the molecular mechanism of memory. J. Biol. Chem. 278, 40305–40316 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Sacktor, T. C. PKMζ, LTP maintenance, and the dynamic molecular biology of memory storage. Prog. Brain Res. 169, 27–40 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Ling, D. S. et al. Protein kinase Mζ is necessary and sufficient for LTP maintenance. Nature Neurosci. 5, 295–296 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Serrano, P., Yao, Y. & Sacktor, T. C. Persistent phosphorylation by protein kinase Mζ maintains late-phase long-term potentiation. J. Neurosci. 25, 1979–1984 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sajikumar, S., Navakkode, S., Sacktor, T. C. & Frey, J. U. Synaptic tagging and cross-tagging: the role of protein kinase Mζ in maintaining long-term potentiation but not long-term depression. J. Neurosci. 25, 5750–5756 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pastalkova, E. et al. Storage of spatial information by the maintenance mechanism of LTP. Science 313, 1141–1144 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Madronal, N., Gruart, A., Sacktor, T. C. & Delgado-Garcia, J. M. PKMzeta inhibition reverses learning-induced increases in hippocampal synaptic strength and memory during trace eyeblink conditioning. PLoS ONE 5, e10400 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Shema, R., Sacktor, T. C. & Dudai, Y. Rapid erasure of long-term memory associations in cortex by an inhibitor of PKMζ. Science 317, 951–953 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Serrano, P. et al. PKMζ maintains spatial, instrumental, and classically conditioned long-term memories. PLoS Biol. 6, 2698–2706 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Shema, R., Hazvi, S., Sacktor, T. C. & Dudai, Y. Boundary conditions for the maintenance of memory by PKMζ in neocortex. Learn. Mem. 16, 122–128 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kwapis, J. L., Jarome, T. J., Lonergan, M. E. & Helmstetter, F. J. Protein kinase Mzeta maintains fear memory in the amygdala but not in the hippocampus. Behav. Neurosci. 123, 844–850 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Migues, P. V. et al. PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nature Neurosci. 13, 630–634 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Hardt, O., Migues, P. V., Hastings, M., Wong, J. & Nader, K. PKMzeta maintains 1-day- and 6-day-old long-term object location but not object identity memory in dorsal hippocampus. Hippocampus 20, 691–695 (2010).

    CAS  PubMed  Google Scholar 

  19. von Kraus, L. M., Sacktor, T. C. & Francis, J. T. Erasing sensorimotor memories via PKMzeta inhibition. PLoS ONE 5, e11125 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sacco, T. & Sacchetti, B. Role of secondary sensory cortices in emotional memory storage and retrieval in rats. Science 329, 649–656 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Pearce, K. C. et al. PKM maintains long-term sensitization in Aplysia. Abstr. Soc. Neurosci. (in the press).

  22. Cai, D. & Glanzman, D. L. Evidence that PKM maintains long-term facilitation in Aplysia. Abstr. Soc. Neurosci. (in the press).

  23. Drier, E. A. et al. Memory enhancement and formation by atypical PKM activity in Drosophila melanogaster. Nature Neurosci. 5, 316–324 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Crick, F. Memory and molecular turnover. Nature 312, 101 (1984).

    Article  CAS  PubMed  Google Scholar 

  25. Schwartz, J. H. & Greenberg, S. M. Molecular mechanisms for memory: second-messenger induced modifications of protein kinases in nerve cells. Annu. Rev. Neurosci. 10, 459–476 (1987).

    Article  CAS  PubMed  Google Scholar 

  26. Lisman, J. E. & Goldring, M. A. Feasibility of long-term storage of graded information by the Ca2+/calmodulin-dependent protein kinase molecules of the postsynaptic density. Proc. Natl Acad. Sci. USA 85, 5320–5324 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Buxbaum, J. D. & Dudai, Y. A quantitative model for the kinetics of cAMP-dependent protein kinase (type II) activity. Long-term activation of the kinase and its possible relevance to learning and memory. J. Biol. Chem. 264, 9344–9351 (1989).

    CAS  PubMed  Google Scholar 

  28. Sacktor, T. C. et al. Persistent activation of the ζ isoform of protein kinase C in the maintenance of long-term potentiation. Proc. Natl Acad. Sci. USA 90, 8342–8346 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nishizuka, Y. The molecular heterogeneity of protein kinase C and its implication for cellular recognition. Nature 334, 661–665 (1988).

    Article  CAS  PubMed  Google Scholar 

  30. Muslimov, I. A. et al. Dendritic transport and localization of protein kinase Mζ mRNA: implications for molecular memory consolidation. J. Biol. Chem. 279, 52613–52622 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Kelly, M. T., Yao, Y., Sondhi, R. & Sacktor, T. C. Actin polymerization regulates the synthesis of PKMζ in LTP. Neuropharmacology 52, 41–45 (2006).

    Article  PubMed  Google Scholar 

  32. Kelly, M. T., Crary, J. F. & Sacktor, T. C. Regulation of protein kinase Mζ synthesis by multiple kinases in long-term potentiation. J. Neurosci. 27, 3439–3444 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Osten, P., Valsamis, L., Harris, A. & Sacktor, T. C. Protein synthesis-dependent formation of protein kinase Mζ in LTP. J. Neurosci. 16, 2444–2451 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Klur, S. et al. Hippocampal-dependent spatial memory functions might be lateralized in rats: an approach combining gene expression profiling and reversible inactivation. Hippocampus 19, 800–816 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Westmark, P. et al. Pin1 and PKMζ sequentially control dendritic protein synthesis. Sci. Signal. 3, ra18 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sacktor, T. C. PINing for things past. Sci. Signal. 3, pe9 (2010).

    Article  PubMed  Google Scholar 

  37. Yao, Y. et al. PKMζ maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors. J. Neurosci. 28, 7820–7827 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Si, K., Lindquist, S. & Kandel, E. R. A neuronal isoform of the aplysia CPEB has prion-like properties. Cell 115, 879–891 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Si, K. et al. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell 115, 893–904 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Miniaci, M. C. et al. Sustained CPEB-dependent local protein synthesis is required to stabilize synaptic growth for persistence of long-term facilitation in Aplysia. Neuron 59, 1024–1036 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mastushita-Sakai, T., White-Grindley, E., Samuelson, J., Seidel, C. & Si, K. Drosophila Orb2 targets genes involved in neuronal growth, synapse formation, and protein turnover. Proc. Natl Acad. Sci. USA 107, 11987–11992 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lagasse, F, Devaud, J. M. & Mery, F. A switch from cycloheximide-resistant consolidated memory to cycloheximide-sensitive reconsolidation and extinction in Drosophila. J. Neurosci. 29, 2225–2230 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Ling, D. S., Benardo, L. S. & Sacktor, T. C. Protein kinase Mζ enhances excitatory synaptic transmission by increasing the number of active postsynaptic AMPA receptors. Hippocampus 16, 443–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Duprat, F., Daw, M., Lim, W., Collingridge, G. & Isaac, J. GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity. Phil. Trans. R. Soc. Lond. B 358, 715–720 (2003).

    Article  CAS  Google Scholar 

  45. Luscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649–658 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Osten, P. et al. The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and α- and β-SNAPs. Neuron 21, 99–110 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Song, I. et al. Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21, 393–400 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Hanley, J. G., Khatri, L., Hanson, P. I. & Ziff, E. B. NSF ATPase and α-/β-SNAPs disassemble the AMPA receptor-PICK1 complex. Neuron 34, 53–67 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Daw, M. I. et al. PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses. Neuron 28, 873–886 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Kim, C. H., Chung, H. J., Lee, H. K. & Huganir, R. L. Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long-term depression. Proc. Natl Acad. Sci. USA 98, 11725–11730 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Emond, M. R. et al. AMPA receptor subunits define properties of state-dependent synaptic plasticity. J. Physiol. 588, 1929–1946 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ahmadian, G. et al. Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J. 23, 1040–1050 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yu, S. Y., Wu, D. C., Liu, L., Ge, Y. & Wang, Y. T. Role of AMPA receptor trafficking in NMDA receptor-dependent synaptic plasticity in the rat lateral amygdala. J. Neurochem. 106, 889–899 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Scholz, R. et al. AMPA receptor signaling through BRAG2 and Arf6 critical for long-term synaptic depression. Neuron 66, 768–780 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Lee, S. H., Liu, L., Wang, Y. T. & Sheng, M. Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron 36, 661–674 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Whitlock, J. R., Heynen, A. J., Shuler, M. G. & Bear, M. F. Learning induces long-term potentiation in the hippocampus. Science 313, 1093–1097 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Gruart, A., Munoz, M. D. & Delgado-Garcia, J. M. Involvement of the CA3–CA1 synapse in the acquisition of associative learning in behaving mice. J. Neurosci. 26, 1077–1087 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tse, D. et al. Schemas and memory consolidation. Science 316, 76–82 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Gerstner, J. R. & Yin, J. C. Circadian rhythms and memory formation. Nature Rev. Neurosci. 11, 577–588 (2010).

    Article  CAS  Google Scholar 

  61. Hrabetova, S. & Sacktor, T. C. Bidirectional regulation of protein kinase Mζ in the maintenance of long-term potentiation and long-term depression. J. Neurosci. 16, 5324–5333 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by the US National Institutes of Health (NIH) (grants R01 MH53576 and MH57068). The article is dedicated to the memory of the late James H. Schwartz, a pioneer in the study of persistent kinases and memory25.

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  1. Departments of Physiology and Pharmacology and of Neurology, Todd C. Sacktor is at The Robert F. Furchgott Center of Neural and Behavioural Science, State University of New York (SUNY) Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA. tsacktor@downstate.edu,

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Consolidated long-term memories disrupted by PKMζ inhibition (PDF 184 kb)

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Glossary

Cellular memory consolidation

The molecular mechanisms that convert memories into an enduring form. The process typically lasts for a few hours after learning and is associated with new protein synthesis. It is distinct from systems memory consolidation, which involves shifts in the neuronal circuitry that subserves a memory and can take weeks or longer.

Long-term memory storage

The physiological mechanism in the brain that perpetuates enduring memories. The storage phase of long-term memory begins from a few hours to a day after learning and can last a lifetime.

Long-term potentiation

A persistent enhancement of excitatory synaptic transmission lasting hours to days, triggered by strong, typically high-frequency, afferent stimulation of the synapse. It is widely studied as a putative physiological basis of long-term memory.

PDZ domain

A common protein structural motif that interacts with specific carboxy-terminal sequences of other proteins. The intracellular distribution and trafficking of many proteins are regulated by their binding to PDZ domain-containing proteins.

Postsynaptic density

A cytoskeletal specialization of the synapse identified by electron microscopy as an electron-dense region at the membrane of the postsynaptic neuron. It concentrates and organizes neurotransmitter receptors, receptor-binding proteins and postsynaptic signalling molecules.

Synaptic tagging

A hypothesis to explain the potentiation during late-LTP (long-term potentiation) of activated synapses by proteins newly synthesized in the neuronal cell body or dendrite. Afferent stimulation sets up a 'tag' specifically at activated synapses that captures the newly synthesized plasticity-related proteins.

Trace eye-blink conditioning

A form of classical conditioning in which the conditioned stimulus (CS; typically an auditory or visual stimulus) precedes the unconditioned stimulus (US; an eye-blink-eliciting stimulus such as a puff of air to the cornea) by a stimulus-free period (trace interval). Trace eye-blink conditioning requires both an intact cerebellum and hippocampus.

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Sacktor, T. How does PKMζ maintain long-term memory?. Nat Rev Neurosci 12, 9–15 (2011). https://doi.org/10.1038/nrn2949

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