In this chapter, we talked about those molecular mechanisms that are uniquely involved in triggering long-lasting and very long-lasting changes in synaptic transmission in the hippocampus. We focused most of our attention on how a signal gets from the synapse to the genome, highlighting the PKA/ERK/RSK/CREB pathway as a principal player in L-LTP. We also touched upon the intriguing problem of how altered gene expression becomes manifest at just the appropriate synapse, looking at Arc mRNA as a prototype molecule.
One of the important ideas that emerged from this chapter was that we need to keep in mind that the available data support the model that altered gene expression is an induction mechanism for L-LTP. The question of whether altered gene expression contributes to the maintenance of L-LTP is still, by and large, an open one at present.
We also talked about how changes in gene expression get manifest as changes at the synapse. We in actuality developed two different models for how this happens. The first was based on increased AMPA
receptors and associated proteins at the synapse, dependent upon a triggering event such as Arc arrival at the synapse. These changes then manifested themselves as an increased synaptic strength. This proposed mechanism is a fairly straightforward read-out of increased production of synaptic components with Arc-like molecules serving as a nucleating event.
However, considering the limitations of proteins like Arc with a half-life of a few hours led us to conclude that later stages of "L-LTP" must involve additional processes. In response to this consideration, we formulated a speculative model for how self-perpetuating changes in local protein synthesis might underlie weeks-long or life-long synaptic changes.
This final section of the chapter brought us back to the issue raised at the very beginning of the chapter, that is, considering "L-LTP" as an analogue of forms of long-term memory that depend on changes in gene expression for their induction. It is very important to remember that the types of synaptic changes we have discussed in this chapter are functionally manifest as an alteration in the properties of a neuronal circuit in the CNS. Clearly, self-perpetuating molecular changes are necessary for very long-lasting effects, but the lasting effects are not the entirety of the memory. The maintenance of the synaptic change in the context of the circuit is what constitutes the memory. The self-perpetuating synaptic change is the mechanism for the maintenance of the memory.
Thus, we see an interesting parallel between L-LTP and long-term memory. Throughout the last three chapters we have made the important molecular distinction between mechanisms for the induction, maintenance, and expression of LTP. We need to make an equally important distinction between the mechanisms for the induction, maintenance, and expression of memory. The induction of memory is learning. The maintenance of long-term memory is self-perpetuating synaptic change in the context of a specific circuit. The expression of memory is the recall of the memory by sending activity through the circuit. Just as it is important to keep in mind the molecular distinctions between the induction, maintenance, and expression of LTP, it is important to keep in mind the molecular distinctions between the induction, maintenance, and expression of long-term memory.
This was an essential point that was made in Chapter 1, where a comparison was made between current learning and memory theory and the changes that need to be made in light of a better understanding of the molecular processes involved in synaptic plasticity. If you have made it this far in the book you have made it through about 75,000 words concerning the gory details of LTP physiology, biochemistry, and molecular biology. You might find it interesting to go back and reread Chapter 1 in light of all the new information you have under your belt.
This analogy between L-LTP and long-term memory is important and valid independently of whether the particular molecular mechanisms for L-LTP that we have been talking about are actually used in the behaving animal for memory itself. That does not mean that this is an uninteresting question, however! In the next chapter we will talk about the evidence for and against a role for LTP specifically in hippocampus-dependent memory formation. We also will discuss the corollary question of whether LTP has accurately modeled memory, that is, are the molecular processes involved in LTP the molecular processes involved in memory?
1. Nguyen, P. V., Abel, T., and Kandel, E. R. (1994). "Requirement of a critical period of transcription for induction of a late phase of LTP." Science 265:1104-1107.
2. Frey, U., Frey, S., Schollmeier, F., and Krug, M. (1996). "Influence of actinomycin D, a RNA
synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro." J. Physiol. 490 (3):703-711.
3. Bourtchuladze, R., Frenguelli, B., Blendy, J., Cioffi, D., Schutz, G., and Silva, A. J. (1994). "Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein." Cell 79:59-68.
4. Gass, P., Wolfer, D. P., Balschun, D., Rudolph, D., Frey, U., Lipp, H. P., and Schutz, G. (1998). "Deficits in memory tasks of mice with CREB mutations depend on gene dosage." Learn. Mem. 5:274-288.
5. Pittenger, C., Huang, Y. Y., Paletzki, R. F., Bourtchouladze, R., Scanlin, H., Vronskaya, S., and Kandel, E. R. (2002). "Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory." Neuron 34:447-462.
6. Jones, M. W., Errington, M. L., French, P. J., Fine, A., Bliss, T. V., Garel, S., Charnay, P., Bozon, B., Laroche, S., and Davis, S. (2001). "A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories." Nat. Neurosci. 4:289-296.
7. Impey, S., Fong, A. L., Wang, Y., Cardinaux, J. R., Fass, D. M., Obrietan, K., Wayman, G. A., Storm, D. R., Soderling, T. R., and Goodman, R. H. (2002). "Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV." Neuron 34:235-244.
8. Kang, H., Sun, L. D., Atkins, C. M., Soderling, T. R., Wilson, M. A., and Tonegawa, S. (2001). "An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory." Cell 106:771-783.
9. English, J. D., and Sweatt, J. D. (1996). "Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation." J. Biol. Chem. 271:24329-24332.
10. English, J. D., and Sweatt, J. D. (1997). "A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation." J. Biol. Chem. 272:19103-19106.
11. Rosenblum, K., Futter, M., Voss, K., Erent, M., Skehel, P. A., French, P., Obosi, L., Jones, M. W., and Bliss, T. V. (2002). "The role of extracellular regulated kinases I/II in late-phase long-term potentiation." J. Neurosci. 22:5432-5441.
12. Impey, S., Obrietan, K., Wong, S. T., Poser, S., Yano, S., Wayman, G., Deloulme, J. C., Chan, G., and Storm, D. R. (1998). "Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation." Neuron 21:869-883.
13. Guzowski, J. F., Lyford, G. L., Stevenson, G. D., Houston, F. P., McGaugh, J. L., Worley, P. F., and Barnes, C. A. (2000). "Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory." J. Neurosci. 20:3993-4001.
14. Barco, A., Alarcon, J. M., and Kandel, E. R. (2002). "Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture." Cell 108:689-703.
15. Brivanlou, A. H., and Darnell, J. E. Jr. (2002). "Signal transduction and the control of gene expression." Science 295:813-818.
16. Shaywitz, A. J., and Greenberg, M. E. (1999). "CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals." Annu. Rev. Biochem. 68:821-861.
17. Poser, S., and Storm, D. R. (2001). "Role of Ca2+-stimulated adenylyl cyclases in LTP and memory formation." Int. J. Dev. Neurosci. 19:387-394.
18. Kornhauser, J. M., Cowan, C. W., Shaywitz, A. J., Dolmetsch, R. E., Griffith, E. C., Hu, L. S., Haddad, C., Xia, Z., and Greenberg, M. E. (2002). "CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phos-phorylation events." Neuron 34:221-233.
19. Ohno, M., Frankland, P. W., Chen, A. P., Costa, R. M., and Silva, A. J. (2001). "Inducible, pharma-cogenetic approaches to the study of learning and memory." Nat. Neurosci. 4:1238-1243.
20. Roberson, E. D., English, J. D., Adams, J. P., Selcher, J. C., Kondratick, C., and Sweatt, J. D. (1999). "The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus." J. Neurosci. 19:4337-4348.
21. Lu, Y. F., Kandel, E. R., and Hawkins, R. D. (1999). "Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus." J. Neurosci. 19:10250-10261.
22. Ho, N., Liauw, J. A., Blaeser, F., Wei, F., Hanissian, S., Muglia, L. M., Wozniak, D. F., Nardi, A., Arvin, K. L., Holtzman, D. M., Linden, D. J., Zhuo, M., Muglia, L. J., and Chatila, T. A. (2000). "Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice." J. Neurosci. 20:6459-6472.
23. Mermelstein, P. G., Deisseroth, K., Dasgupta, N., Isaksen, A. L., and Tsien R. W. (2001). "Calmodulin priming: nuclear translocation of a calmodulin complex and the memory of prior neuronal activity." Proc. Natl. Acad. Sci. USA 98:15342-15347.
24. Deisseroth, K., Bito, H., and Tsien, R. W. (1996). "Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity." Neuron 16:89-101.
25. Deisseroth, K., and Tsien, R. W. (2002). "Dynamic multiphosphorylation passwords for activity-dependent gene expression." Neuron 34:179-182.
26. Dudek, S. M., and Fields, R. D. (2002). "Somatic action potentials are sufficient for late-phase LTP-related cell signaling." Proc. Natl. Acad. Sci. USA 99:3962-3967.
27. Gooney, M., and Lynch, M. A. (2001). "Long-term potentiation in the dentate gyrus of the rat hippocampus is accompanied by brain-derived neurotrophic factor-induced activation of TrkB." J. Neurochem. 7:1198-1207.
28. Hall, J., Thomas, K. L., and Everitt, B. J. (2000). "Rapid and selective induction of BDNF expression in the hippocampus during contextual learning." Nat. Neurosci. 3:533-535.
29. Yin, Y., Edelman, G. M., and Vanderklish, P. W. (2002). "The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes." Proc. Natl. Acad. Sci. USA 99:2368-2373.
30. Patterson, S. L., Pittenger, C., Morozov, A., Martin, K. C., Scanlin, H., Drake, C., and Kandel, E. R. (2001). "Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase." Neuron 32:123-140.
31. Ying, S. W., Futter, M., Rosenblum, K., Webber, M. J., Hunt, S. P., Bliss, T. V., and Bramham, C. R. (2002). "Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis." J. Neurosci. 22:1532-1540.
32. Matthies, H., Becker, A., Schroeder, H., Kraus, J., Hollt, V., and Krug, M. (1997). "Dopamine D1-deficient mutant mice do not express the late phase of hippocampal long-term potentiation." Neuroreport 8:3533-3535.
33. Wu, L., Wells, D., Tay, J., Mendis, D., Abbott, M. A., Barnitt, A., Quinlan, E., Heynen, A., Fallon, J. R., and Richter, J. D. (1998). "CPEB-mediated cyto-plasmic polyadenylation and the regulation of experience-dependent translation of alpha-CaMKII mRNA at synapses." Neuron 21:1129-1139.
34. Schulz, S., Siemer, H., Krug, M., and Hollt, V. (1999). "Direct evidence for biphasic cAMP responsive element-binding protein phosphory-lation during long-term potentiation in the rat dentate gyrus in vivo." J. Neurosci. 19:5683-5692.
35. Davis, S., Vanhoutte, P., Pages, C., Caboche, J., and Laroche, S. (2000). "The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo." J. Neurosci. 20:4563-4572.
36. Waltereit, R., Dammermann, B., Wulff, P., Scafidi, J., Staubli, U., Kauselmann, G., Bundman, M., and Kuhl, D. (2001). "Arg3.1 /Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation." J. Neurosci. 21:5484-5493.
37. Mattson, M. P., Culmsee, C., Yu, Z., and Camandola, S. (2000). "Roles of nuclear factor kappaB in neuronal survival and plasticity." J. Neurochem. 74:443-456.
38. Albensi, B. C., and Mattson, M. P. (2000). "Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity." Synapse 35:151-159.
39. Meberg, P. J., Kinney, W. R., Valcourt, E. G., and Routtenberg, A. (1996). "Gene expression of the transcription factor NF-kappa B in hippocampus: regulation by synaptic activity." Brain Res. Mol. Brain Res. 38:179-190.
40. Cole, A. J., Saffen, D. W., Baraban, J. M., and Worley, P. F. (1989). "Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation." Nature 340:474-476.
41. Wisden, W., Errington, M. L., Williams, S., Dunnett, S. B., Waters, C., Hitchcock, D., Evan, G., Bliss, T. V., and Hunt, S. P. (1990). "Differential expression of immediate early genes in the hippocampus and spinal cord." Neuron 4:603-614.
42. Abraham, W. C., Dragunow, M., and Tate, W. P. (1991). "The role of immediate early genes in the stabilization of long-term potentiation." Mol. Neurobiol. 5:297-314.
43. Abraham, W. C., Mason, S. E., Demmer, J., Williams, J. M., Richardson, C. L., Tate, W. P., Lawlor, P. A., and Dragunow, M. (1993). "Correlations between immediate early gene induction and the persistence of long-term potentiation." Neuroscience 56:717-727.
44. Williams, J., Dragunow, M., Lawlor, P., Mason, S., Abraham, W. C., Leah, J., Bravo, R., Demmer, J., and Tate, W. (1995). "Krox20 may play a key role in the stabilization of long-term potentiation." Brain Res. Mol. Brain Res. 28:87-93.
45. Taubenfeld, S. M., Wiig, K. A., Monti, B., Dolan, B., Pollonini, G., and Alberini, C. M. (2001). "Fornix-dependent induction of hippocampal CCAAT enhancer-binding protein [beta] and [delta] Co-localizes with phosphorylated cAMP response element-binding protein and accompanies long-term memory consolidation." J. Neurosci. 21:84-91.
46. Patterson, S. L., Grover, L. M., Schwartzkroin, P. A., and Bothwell, M. (1992). "Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs." Neuron 9:1081-1088.
47. Huang, Y. Y., Bach, M. E., Lipp, H. P., Zhuo, M., Wolfer, D. P., Hawkins, R. D., Schoonjans, L., Kandel, E. R., Godfraind, J. M., Mulligan, R., Collen, D., and Carmeliet, P. (1996). "Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways." Proc. Natl. Acad. Sci. USA 93:8699-8704.
48. Szklarczyk, A., Lapinska, J., Rylski, M., McKay, R. D., and Kaczmarek, L. (2002). "Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus." J. Neurosci. 22:920-930.
49. Ingi, T., Worley, P. F., and Lanahan, A. A. (2001). "Regulation of SSAT expression by synaptic activity." Eur. J. Neurosci. 13:1459-1463.
50. Qian, Z., Gilbert, M., and Kandel, E. R. (1994). "Temporal and spatial regulation of the expression of BAD2, a MAP kinase phosphatase, during seizure, kindling, and long-term potentiation." Learn. Mem. 1:180-188.
51. Nayak, A., Zastrow, D. J., Lickteig, R., Zahniser, N. R., and Browning, M. D. (1998). "Maintenance of late-phase LTP is accompanied by PKA-dependent increase in AMPA receptor synthesis." Nature 394:680-683.
52. Kato, A., Ozawa, F., Saitoh, Y., Hirai, K., and Inokuchi, K. (1997). "vesl, a gene encoding VASP/ Ena family related protein, is upregulated during seizure, long-term potentiation and synapto-genesis." FEBS Lett. 412:183-189.
53. Matsuo, R., Murayama, A., Saitoh, Y., Sakaki, Y., and Inokuchi, K. (2000). "Identification and cataloging of genes induced by long-lasting long-term potentiation in awake rats." J. Neurochem. 74:2239-2249.
54. Steward, O., and Worley, P. F. (2001). "Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation." Neuron 30:227-240.
55. Bolshakov, V. Y., Golan, H., Kandel, E. R., and Siegelbaum, S. A. (1997). "Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3-CA1 synapses in the hippocampus." Neuron 19:635-651.
56. Luscher, C., Nicoll, R. A., Malenka, R. C., and Muller, D. (2000). "Synaptic plasticity and dynamic modulation of the postsynaptic membrane." Nat. Neurosci. 3:545-550.
57. Steward, O., and Worley, P. F. (2001). "A cellular mechanism for targeting newly synthesized mRNAs to synaptic sites on dendrites." Proc. Natl. Acad. Sci. USA 98:7062-7068.
58. Steward, O., and Schuman, E. M. (2001). "Protein synthesis at synaptic sites on dendrites." Annu. Rev. Neurosci. 4:299-325.
59. Link, W., Konietzko, U., Kauselmann, G., Krug, M., Schwanke, B., Frey, U., and Kuhl, D. (1995). "Somatodendritic expression of an immediate early gene is regulated by synaptic activity." Proc. Natl. Acad. Sci. USA 92:5734-5738.
60. Khan, A., Pepio, A. M., and Sossin, W. S. (2001). "Serotonin activates S6 kinase in a rapamycin-sensitive manner in Aplysia synaptosomes." J. Neurosci. 21:382-391.
61. Raught, B., Gin gras, A. C., and Sonenberg, N. (2001). "The target of rapamycin (TOR) proteins." Proc. Natl. Acad. Sci. USA 98:7037-7044.
62. Tang, S. J., Meulemans, D., Vazquez, L., Colaco, N., and Schuman, E. (2001). "A role for a rat homolog of staufen in the transport of RNA to neuronal dendrites." Neuron 32:463-475.
63. Engert, F., and Bonhoeffer, T. (1999). "Dendritic spine changes associated with hippocampal long-term synaptic plasticity." Nature 399:66-70.
64. Maletic-Savatic, M., Malinow, R., and Svoboda, K. (1999). "Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity." Science 283:1923-1927.
65. Toni, N., Buchs, P. A., Nikonenko, I., Bron, C. R., and Muller, D. (1999). "LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite." Nature 402:421-425.
66. Yuste, R., and Bonhoeffer, T. (2001). "Morphological changes in dendritic spines associated with long-term synaptic plasticity." Annu. Rev. Neurosci. 24:1071-1089.
67. Bozdagi, O., Shan, W., Tanaka, H., Benson, D. L., and Huntley, G. W. (2000). "Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation." Neuron 28:245-259.
68. Tang, L., Hung, C. P., and Schuman, E. M. (1998). "A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentia-tion." Neuron 20:1165-1175.
69. Chun, D., Gall, C. M., Bi, X., and Lynch, G. (2001). "Evidence that integrins contribute to multiple stages in the consolidation of long term poten-tiation in rat hippocampus." Neuroscience 105:815-829.
70. Kramar, E. A., Bernard, J. A., Gall, C. M., and Lynch, G. (2002). "Alpha3 integrin receptors contribute to the consolidation of long-term potentiation." Neuroscience 110:29-39.
71. Bliss, T., Errington, M., Fransen, E., Godfraind, J. M., Kauer, J. A., Kooy, R. F., Maness, P. F., and Furley, A. J. (2000). "Long-term potentiation in mice lacking the neural cell adhesion molecule L1." Curr. Biol. 10:1607-1610.
72. Juliano, R. L. (2002). "Signal transduction by cell adhesion receptors and the cytoskeleton:
functions of integrins, Cadherins, selectins, and immunoglobulin-superfamily members." Annu. Rev. Pharmacol. Toxicol. 42:283-323.
73. Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A. M., Nordborg, C., Peterson, D. A., and Gage, F. H. (1998). "Neurogenesis in the adult human hippocampus." Nat. Med. 4:1313-1317.
74. Gould, E., Beylin, A., Tanapat, P., Reeves, A., and Shors, T. J. (1999). "Learning enhances adult neurogenesis in the hippocampal formation." Nat. Neurosci. 2:260-265.
75. Villarreal, D. M., Do, V., Haddad, E., and Derrick, B. E. (2002). "NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay." Nat. Neurosci. 5:48-52.
76. Frey, U., Krug, M., Reymann, K. G., and Matthies, H. (1988). "Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro." Brain Res. 452:57-65.
77. Nguyen, P. V., and Kandel, E. R. (1997). "Brief theta-burst stimulation induces a transcription-dependent late phase of LTP requiring cAMP in area CA1 of the mouse hippocampus." Learn. Mem. 4:230-243.
78. Wei, F., Qiu, C. S., Liauw, J., Robinson, D. A., Ho, N., Chatila, T., and Zhuo, M. (2002). "Calcium calmodulin-dependent protein kinase IV is required for fear memory." Nat. Neurosci. 5:573-579.
79. Impey, S., Mark, M., Villacres, E. C., Poser, S., Chavkin, C., and Storm, D. R. (1996). "Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus." Neuron 16:973-982.
80. Gartner, A., and Staiger, V. (2002). "Neurotrophin secretion from hippocampal neurons evoked by long-term-potentiation-inducing electrical stimulation patterns." Proc. Natl. Acad. Sci. USA 99:6386-6391.
81. Roberts, L. A., Large, C. H., Higgins, M. J., Stone, T. W., O'Shaughnessy, C. T., and Morris B. J. (1998). "Increased expression of dendritic mRNA following the induction of long-term potentia-tion." Brain Res. Mol. Brain Res. 56:38-44.
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