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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References
Kandel, E. R. & Schwartz, J. H. Molecular biology of learning: modulation of transmitter release. Science 218, 433–443 (1982).
Dudai, Y. Neurogenetic dissection of learning and short-term memory in Drosophila. Annu. Rev. Neurosci. 11, 537–563 (1988).
Sanes, J. R. & Lichtman, J. W. Can molecules explain long-term potentiation? Nature Neurosci. 2, 597–604 (1999).
Nader, K., Schafe, G. E. & LeDoux, J. E. The labile nature of consolidation theory. Nature Rev. Neurosci. 1, 216–219 (2000).
Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).
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).
Sacktor, T. C. PKMζ, LTP maintenance, and the dynamic molecular biology of memory storage. Prog. Brain Res. 169, 27–40 (2008).
Ling, D. S. et al. Protein kinase Mζ is necessary and sufficient for LTP maintenance. Nature Neurosci. 5, 295–296 (2002).
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).
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).
Pastalkova, E. et al. Storage of spatial information by the maintenance mechanism of LTP. Science 313, 1141–1144 (2006).
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).
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).
Serrano, P. et al. PKMζ maintains spatial, instrumental, and classically conditioned long-term memories. PLoS Biol. 6, 2698–2706 (2008).
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).
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).
Migues, P. V. et al. PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nature Neurosci. 13, 630–634 (2010).
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).
von Kraus, L. M., Sacktor, T. C. & Francis, J. T. Erasing sensorimotor memories via PKMzeta inhibition. PLoS ONE 5, e11125 (2010).
Sacco, T. & Sacchetti, B. Role of secondary sensory cortices in emotional memory storage and retrieval in rats. Science 329, 649–656 (2010).
Pearce, K. C. et al. PKM maintains long-term sensitization in Aplysia. Abstr. Soc. Neurosci. (in the press).
Cai, D. & Glanzman, D. L. Evidence that PKM maintains long-term facilitation in Aplysia. Abstr. Soc. Neurosci. (in the press).
Drier, E. A. et al. Memory enhancement and formation by atypical PKM activity in Drosophila melanogaster. Nature Neurosci. 5, 316–324 (2002).
Crick, F. Memory and molecular turnover. Nature 312, 101 (1984).
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).
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).
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).
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).
Nishizuka, Y. The molecular heterogeneity of protein kinase C and its implication for cellular recognition. Nature 334, 661–665 (1988).
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).
Kelly, M. T., Yao, Y., Sondhi, R. & Sacktor, T. C. Actin polymerization regulates the synthesis of PKMζ in LTP. Neuropharmacology 52, 41–45 (2006).
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).
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).
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).
Westmark, P. et al. Pin1 and PKMζ sequentially control dendritic protein synthesis. Sci. Signal. 3, ra18 (2010).
Sacktor, T. C. PINing for things past. Sci. Signal. 3, pe9 (2010).
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).
Si, K., Lindquist, S. & Kandel, E. R. A neuronal isoform of the aplysia CPEB has prion-like properties. Cell 115, 879–891 (2003).
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).
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).
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).
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).
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).
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).
Luscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649–658 (1999).
Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 (1998).
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).
Song, I. et al. Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21, 393–400 (1998).
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).
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).
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).
Emond, M. R. et al. AMPA receptor subunits define properties of state-dependent synaptic plasticity. J. Physiol. 588, 1929–1946 (2010).
Ahmadian, G. et al. Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J. 23, 1040–1050 (2004).
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).
Scholz, R. et al. AMPA receptor signaling through BRAG2 and Arf6 critical for long-term synaptic depression. Neuron 66, 768–780 (2010).
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).
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).
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).
Tse, D. et al. Schemas and memory consolidation. Science 316, 76–82 (2007).
Gerstner, J. R. & Yin, J. C. Circadian rhythms and memory formation. Nature Rev. Neurosci. 11, 577–588 (2010).
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).
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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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
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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
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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
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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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DOI: https://doi.org/10.1038/nrn2949
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