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  • Review Article
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Is Heterosynaptic modulation essential for stabilizing hebbian plasiticity and memory

Nature Reviews Neuroscience volume 1, pages 11–20 (2000)Cite this article

Abstract

In 1894, Ramón y Cajal first proposed that memory is stored as an anatomical change in the strength of neuronal connections. For the following 60 years, little evidence was recruited in support of this idea. This situation changed in the middle of the twentieth century with the development of cellular techniques for the study of synaptic connections and the emergence of new formulations of synaptic plasticity that redefined Ramón y Cajal's idea, making it more suitable for testing. These formulations defined two categories of plasticity, referred to as homosynaptic or Hebbian activity-dependent, and heterosynaptic or modulatory input-dependent. Here we suggest that Hebbian mechanisms are used primarily for learning and for short-term memory but often cannot, by themselves, recruit the events required to maintain a long-term memory. In contrast, heterosynaptic plasticity commonly recruits long-term memory mechanisms that lead to transcription and to synaptic growth. When jointly recruited, homosynaptic mechanisms assure that learning is effectively established and heterosynaptic mechanisms ensure that memory is maintained.

Key Points

  • Modern formulations of synaptic plasticity have led to the definition of two broad categories — homosynaptic or Hebbian activity-dependent and heterosynaptic or modulatory input-dependent. In homosynaptic plasticity, the events responsible for triggering the plastic change occur at the same connection being strengthened or weakened. In heterosynaptic plasticity, the plastic change can occur in the absence of activity of the synapse being strengthened but, instead, as a result of a third, modulatory interneuron.

  • Homosynaptic Hebbian plasticity in both invertebrate and in mammalian synapses involves the covalent modification of pre-existing synaptic proteins and, when initiated by itself, it often lasts only for one or at most a few hours. In contrast, heterosynaptic mechanisms can readily lead to plastic changes that last for one or more days and can, by themselves, recruit the cellular machinery necessary for the synthesis of new proteins and for the growth of new synapses.

  • In invertebrate (Aplysia) synapses, the combination of homo- and heterosynaptic mechanisms can result in new categories of synaptic plasticity. For example, when recruited together, the duration of the plastic change can increase in a non-additive way. In addition, the combined mechanisms can restrict the long-term plastic change to a set of synapses smaller than either mechanism alone, thereby sharpening its synapse-specificity.

  • A similar interaction between homosynaptic and heterosynaptic mechanisms might occur in mammalian synapses but a rigorous demonstration is still missing. Nevertheless, the observation that the blockade of modulatory neurotransmitters prevents the generation of long-lasting changes of synaptic strength indicates that heterosynaptic plasticity probably also contributes to the stabilization of short-term memory in the mammalian brain.

  • One possible functional significance of this interaction is that homosynaptic mechanisms are used by the nervous system to ensure that learning is effectively established; once learning has taken place, heterosynaptic mechanisms ensure that a long-term memory is maintained.

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Figure 1: Homosynaptic and heterosynaptic mechanisms for long-term plasticity.
Figure 2: Modulatory transmitters enhance the duration of long-term potentiation.
Figure 3: Comparison of homosynaptic facilitation with paired homo- and heterosynaptic facilitation.
Figure 4: Non-additive interaction of homo- and heterosynaptic plasticity.
Figure 5: Interaction of homo- and heterosynaptic mechanisms sharpens long-term synapse specificity.

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References

  1. Ramón y Cajal, S. La fine structure des centres nerveux. Proc. R. Soc. Lond. 55, 444–468 (1894).

    Article  Google Scholar 

  2. Konorski, J. Conditioned Reflexes and Neuron Organization (Cambridge Univ. Press, London, 1948).

    Google Scholar 

  3. Hebb, D. O. The Organization of Behavior: A Neuropsychological Theory (Wiley, New York, 1949).An influential discussion on the neural control of perception and action, which includes a consideration of a homosynaptic (activity-dependent) rule for long-term memory.

    Google Scholar 

  4. Kandel, E. R. & Spencer, W. A. Cellular neurophysiological approaches in the study of the learning. Physiol. Rev. 48, 65–134 (1968).An early review outlining cellular approaches to the long-term plastic capabilities of chemical synapses and their role in learning and memory.

    Article  CAS  PubMed  Google Scholar 

  5. Cowan, M. & Kandel, E. R. in The Synapse (John Hopkins, Baltimore, in the press).

  6. Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361 , 31–39 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Malenka, R. C. & Nicoll, R. A. Long-term potentiation – a decade of progress. Science 17, 1870– 1874 (1999).References 6 and 7 are two classic summaries of the state of research on E-LTP.

    Article  Google Scholar 

  8. Kandel, E. R. & Tauc, L. Heterosynaptic facilitation in neurones of the abdominal ganglion of Aplysia depilans. J. Physiol. (Lond.) 181, 1–27 ( 1965).

    Article  CAS  Google Scholar 

  9. Kandel, E. R. & Tauc, L. Mechanism of heterosynaptic facilitation in the giant cell of the abdominal ganglion of Aplysia depilans. J. Physiol. (Lond.) 181, 28–47 (1965).References 8 and 9 introduce the heterosynaptic (modulatory input-dependent) rule for long-term memory.

    Article  CAS  Google Scholar 

  10. Dudel, J. & Kuffler, S. Presynaptic inhibition at the crayfish neuromuscular junction. J. Physiol. (Lond.) 155, 543–562 (1961).

    Article  CAS  Google Scholar 

  11. Kupfermann, I., Castellucci, V., Pinsker, H. & Kandel, E. R. Neuronal correlates of habituation and dishabituation of the gill-withdrawal reflex in Aplysia. Science 167, 1743 –1745 (1970).

    Article  CAS  PubMed  Google Scholar 

  12. Pinsker, H., Kupfermann, I., Castellucci, V. & Kandel, E. R. Habituation and dishabituation of the gill-withdrawal reflex in Aplysia . Science 167, 1740– 1742 (1970).References 11 and 12 were the first systematic attempts to address the questions of behavioural relevance and time course of synaptic plasticity related to memory storage at the level of single identified nerve cells.

    Article  CAS  PubMed  Google Scholar 

  13. Castellucci, V., Pinsker, H., Kupfermann, I. & Kandel, E. R. Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in Aplysia. Science 167, 1745 –1748 (1970).

    Article  CAS  PubMed  Google Scholar 

  14. Hawkins, R. D., Castellucci, V. F. & Kandel, E. R. Interneurons involved in mediation and modulation of the gill-withdrawal reflex in Aplysia. II. Identified neurons produce heterosynaptic facilitation contributing to behavioral sensitization. J. Neurophysiol. 45, 315–326 (1981).

    Article  CAS  PubMed  Google Scholar 

  15. Dale, N. & Kandel, E. R. l-glutamate may be the fast excitatory transmitter of Aplysia sensory neurons. Proc. Natl Acad. Sci. USA 90, 7163– 7167 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Trudeau, L. E. & Castellucci, V. F. Postsynaptic modifications in long-term facilitation in upregulation of excitatory amino acid receptors. J. Neurosci. 15, 1275– 1284 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Frost, L. et al. A simplified preparation for relating cellular events to behavior: contribution of LE and unidentified siphon sensory neurons to mediation and habituation of the Aplysia gill- and siphon-withdrawal reflex. J. Neurosci. 17, 2900–2913 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Antonov, I., Kandel, E. R. & Hawkins, R. D. The contribution of facilitation of monosynaptic PSPs to dishabituation and sensitization of the Aplysia siphon-withdrawal reflex. J. Neurosci. 19, 10438– 10450 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Castellucci, V. & Kandel, E. R. A quantal analysis of the synaptic depression underlying habituation of the gill-withdrawal reflex in Aplysia. Proc. Natl Acad. Sci. USA 71, 5004–5008 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Carew, T. J., Castellucci, V. F. & Kandel, E. R. An analysis of dishabituation and sensitization of the gill-withdrawal reflex in Aplysia. Int. J. Neurosci. 2, 79–98 (1971 ).

    Article  CAS  PubMed  Google Scholar 

  21. Pinsker, H. M., Hening, W. A., Carew, T. J. & Kandel, E. R Long-term sensitization of a defensive withdrawal reflex in Aplysia. Science 182, 1039–1042 ( 1973).

    Article  CAS  PubMed  Google Scholar 

  22. Castellucci, V. & Kandel, E. R. Presynaptic facilitation as a mechanism for behavioral sensitization in Aplysia. Science 194, 1176–1178 ( 1976).

    Article  CAS  PubMed  Google Scholar 

  23. Glanzman, D. L. et al. Depletion of serotonin in the nervous system of Aplysia reduces the behavioral enhancement of gill withdrawal as well as the heterosynaptic facilitation produced by tail shock. J. Neurosci. 9, 4200–4213 ( 1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brunelli, M., Castellucci, V. & Kandel, E. R. Synaptic facilitation and behavioral sensitization in Aplysia: possible role of serotonin and cyclic AMP. Science 194, 1178–1181 ( 1976).

    Article  CAS  PubMed  Google Scholar 

  25. Braha, O. et al. Second messengers involved in the two processes of presynaptic facilitation that contribute to sensitization and dishabituation in Aplysia sensory neurons. Proc. Natl Acad. Sci. USA 87, 2040–2044 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hawkins, R. D., Kandel, E. R. & Siegelbaum, S. A. Learning to modulate transmitter release: themes and variations in synaptic plasticity. Annu. Rev. Neurosci. 16, 625–665 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Byrne, J. H. & Kandel, E. R. Presynaptic facilitation revisited: state and time dependence. J. Neurosci. 16, 425–435 (1995).

    Article  Google Scholar 

  28. Müller, U. & Carew, T. J. Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons. Neuron 21, 1423–1434 (1998).

    Article  PubMed  Google Scholar 

  29. Goelet, P., Castellucci, V. F., Schacher, S. & Kandel, E. R. The long and the short of long-term memory – a molecular framework. Nature 322, 419–422 ( 1986).An introduction to the molecular mechanisms for long-term memory storage.

    Article  CAS  PubMed  Google Scholar 

  30. Davis, H. P. & Squire, L. R. Protein synthesis and memory: a review. Psychol. Bull. 96, 518– 559 (1984).

    Article  CAS  PubMed  Google Scholar 

  31. Frost, W. N., Castellucci, V. F., Hawkins, R. D. & Kandel, E. R. Monosynaptic connections from the sensory neurons of the gill- and siphon-withdrawal reflex in Aplysia participate in the storage of long-term memory for sensitization. Proc. Natl Acad. Sci. USA 82, 8266–8269 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Castellucci, V. F., Blumenfeld, H., Goelet, P. & Kandel, E. R. Inhibitor of protein synthesis blocks long-term behavioral sensitization in the isolated gill-withdrawal reflex of Aplysia. J. Neurobiol. 20, 1–9 (1989 ).

    Article  CAS  PubMed  Google Scholar 

  33. Montarolo, P. G. et al. A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia. Science 234, 1249–1254 (1986).

    Article  CAS  PubMed  Google Scholar 

  34. Rayport, S. G. & Schacher, S. Synaptic plasticity in vitro: cell culture of identified Aplysia neurons mediating short-term habituation and sensitization. J. Neurosci. 6, 759–763 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Martin, K. C. et al. Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91, 927–938 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Schacher, S., Castellucci, V. F. & Kandel, E. R. cAMP evokes long-term facilitation in Aplysia sensory neurons that requires new protein synthesis. Science 240, 1667–1669 ( 1988).

    Article  CAS  PubMed  Google Scholar 

  37. Scholz, K. P. & Byrne, J. H. Intracellular injection of cAMP induces a long-term reduction of neuronal K+ currents. Science 240, 1664–1666 ( 1988).

    Article  CAS  PubMed  Google Scholar 

  38. Ghirardi, M. et al. Roles of PKA and PKC in facilitation of evoked and spontaneous transmitter release at depressed and nondepressed synapses in Aplysia sensory neurons. Neuron 9, 479– 489 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Carew, T. J. Molecular enhancement of memory formation. Neuron 16 , 5–8 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Martin, K. et al. MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Neuron 18, 899–912 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  41. Dash, P. K., Hochner, B. & Kandel, E. R. Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345, 718–721 ( 1990).

    Article  CAS  PubMed  Google Scholar 

  42. Bacskai, B. J. et al. Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons. Science 260, 222–226 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Kaang, B. K., Kandel, E. R. & Grant, S. G. N. Activation of cAMP-responsive genes by stimuli that produce long-term facilitation in Aplysia sensory neurons. Neuron 10, 427–435 ( 1993).

    Article  CAS  PubMed  Google Scholar 

  44. Alberini, C. M., Ghirardi, M., Metz, R. & Kandel, E. R. C/EBP is an immediate-early gene required for the consolidation of long-term facilitation in Aplysia. Cell 76, 1099– 1114 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Bartsch, D. et al. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 83, 979– 992 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Bartsch, D., Casadio, A., Karl, K. A., Serodio, P. & Kandel, E. R. CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation. Cell 95, 211– 223 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Glanzman, D. L., Kandel, E. R. & Schacher, S. Target-dependent structural changes accompanying long-term synaptic facilitation in Aplysia neurons. Science 249, 799–802 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Bailey, C. H., Montarolo, P., Chen, M., Kandel, E. R. & Schacher, S. Inhibitors of protein and RNA synthesis block structural changes that accompany long-term heterosynaptic plasticity in Aplysia. Neuron 9, 749–758 ( 1992).

    Article  CAS  PubMed  Google Scholar 

  49. Bailey, C. H. & Chen, M. Morphological basis of long-term habituation and sensitization in Aplysia. Science 220, 91–93 (1983).

    Article  CAS  PubMed  Google Scholar 

  50. Bailey, C. H. & Chen, M. Long-term memory in Aplysia modulates the total number of varicosities of single identified sensory neurons . Proc. Natl Acad. Sci. USA 85, 2373– 2377 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bailey, C. H. & Chen, M. Time course of structural changes at identified sensory neuron synapses during long-term sensitization in Aplysia . J. Neurosci. 9, 1774– 1780 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Montarolo, P. G., Kandel, E. R. & Schacher, S. Long-term heterosynaptic inhibition in Aplysia. Nature 333, 171–174 ( 1988).

    Article  CAS  PubMed  Google Scholar 

  53. Bliss, T. V. P. & Lømo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. (Lond.) 232, 331–356 ( 1973).The first description of long-term potentiation.

    Article  CAS  Google Scholar 

  54. Milner, B., Squire, L. R. & Kandel, E. R. Cognitive neuroscience and the study of memory. Review . Neuron 20, 445–468 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Gustafsson, B. & Wigstrom, H. Physiological mechanisms underlying long-term potentiation. Trends Neurosci. 11, 156–162 ( 1988).The first rigorous attempt to correlate Hebbian homosynaptic plasticity to long-term potentiation.

    Article  CAS  PubMed  Google Scholar 

  56. Kauer, J. A., Malenka, R. C. & Nicoll, R. A. A persistent postsynaptic modification mediates long-term potentiation in hippocampus. Neuron 10, 911–917 (1988).

    Article  Google Scholar 

  57. Rogan, M. T. & LeDoux, J. E. LTP is accompanied by commensurate enhancement of auditory-evoked responses in a fear conditioning circuit. Neuron 15, 127–136 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  58. Salen, P. A., Malenka, R. C. & Nicoll, R. A. Cyclic AMP mediates a presynaptic form of LTP at cerebellar parallel fiber synapses. Neuron 16, 747–803 (1996).

    Google Scholar 

  59. Vickery, R. M., Shanida, H., Morris, H. & Bindman, L. J. Metabotropic glutamate receptors are involved in long-term potentiation in isolated slices of rat medial frontal cortex. J. Neurophysiol. 78, 3039–3046 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Linden, D. J. & Ahn, S. Activation of presynaptic cAMP-dependent-protein kinase is required for induction of cerebellar long-term potentiation. J. Neurosci. 19, 10221–10227 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Frey, U., Krug, M., Reymann, K. G. & Matthies, H. Anisomycin, an inhibitor of protein synthesis, blocks the late phases of LTP phenomena in the hippocampal CA1 region. Brain Res. 452, 57–65 (1988).

    Article  CAS  PubMed  Google Scholar 

  62. Nguyen, P. V., Abel, T. & Kandel, E. R. Requirement of a critcal period of transcription for induciton of a late phase of LTP. Science 26, 1104–1107 (1994).

    Article  Google Scholar 

  63. Huang, Y.-Y., Nguyen, P. V., Abel, T. & Kandel, E. R. Long-lasting forms of synaptic potentiation in the mammalian hippocampus. Learn. Mem. 3, 74–85 ( 1996).Summary of molecular mechanisms underlying long-lasting forms of synaptic potentiation in the hippocampus.

    Article  CAS  PubMed  Google Scholar 

  64. Frey, U., Frey, S., Schollmeier, F. & Krug, M. Influence of actinomycin D, an RNA synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro. J. Physiol. (Lond.) 490, 703–711 (1996).

    Article  CAS  Google Scholar 

  65. Frey, U., Huang, Y.-Y. & Kandel, E. R. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 260, 1661– 1664 (1993).

    Article  CAS  PubMed  Google Scholar 

  66. Huang, Y.-Y. & Kandel, E. R. Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. Learn. Mem. 1, 74–82 (1994).

    CAS  PubMed  Google Scholar 

  67. Atkins, C. M., Selcher, J. C., Petraitis, J. J., Trzaskos, J. M. & Sweatt, J. D. The MAPK cascade is required for mammalian associative learning. Nature Neurosci. 7, 602–609 ( 1998).

    Article  Google Scholar 

  68. Sweatt, J. D. Toward a molecular explanation for long-term potentiation. Learn. Mem. 5, 399–416 ( 1999).

    Article  Google Scholar 

  69. Huang, Y.-Y., Li, X.-C. & Kandel, E. R. cAMP contributes to mossy fiber LTP by initiating both a covalently-mediated early phase and macromolecular synthesis-dependent late phase. Cell 79, 69–79 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Huang, Y.-Y. et al. A genetic test of the effects of mutations in PKA on mossy fiber LTP and its relation to spatial and contextual learning. Cell 83, 1211–1222 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  71. Huang, Y.-Y., Martin, K. C. & Kandel, E. R. Both PKA and MAP kinase are required for the macromolecular synthesis-dependent late phase of LTP in the amygdala. J. Neurosci. (in the press).

  72. Impey, S. et al. Induction of CRE-mediated gene expression by stimuli that generate long–lasting LTP in area CA1 of the hippocampus. Neuron 16, 973–982 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Abel, T. et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88, 615–626 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Otmakhova, N. A., Otmakhov, N., Mortenson, L. H. & Lisman, J. E. Inhibition of the cAMP pathway decreases early long-term potentiation at CA1 hippocampal synapses. J. Neurosci. 20, 4446 –4451 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Impey, S. et al. Stimulation of cAMP Response Element (CRE)-mediated transcription during contextual learning. Nature Neurosci. 7, 595–601 (1998).

    Article  Google Scholar 

  76. Bourtchouladze, R. et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 59–68 (1994).

    Article  Google Scholar 

  77. Kida, S. Kogan, J. H., Yokoi, T., Masushige, S. & Silva, A. J. Analysis of role and function of CREB signaling pathway during the formation of long–term memory (LTM). Soc. Neurosci. Abstr. 24, 440 (1998).

    Google Scholar 

  78. Josselyn, S. A., Kida, S. & Silva, A. J. CREB and long–term memory for conditioned taste aversion. Soc. Neurosci. Abstr. 25, 645 (2000).

    Google Scholar 

  79. Pittenger, C., Scanlin, H., Huang, Y.-Y., Abel, T. & Kandel, E. R. Expression of a dominant–negative CREB mutant restricted in the hippocampus to the dorsal portion of the CA1 region demonstrates a role for CREB in spatial learning. Soc. Neurosci. Abstr. (in the press).

  80. Gass, P. et al. Deficits in memory tasks of mice with CREB mutations depend on gene dosage. Learn. Mem. 5, 274– 288 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Bartsch, D. et al. Enhancement of memory related and CREB1-dependent long-term facilitation in Aplysia sensory neurons by overexpression of Aplysia Activating Factor, a novel leucine–zipper transcription factor. Cell (in the press).

  82. Impey, S. et al. Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation . Neuron 21, 869–883 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Zamanillo, D. et al. Importance of AMPA receptors for hippocampal LTP but not for spatial learning. Science 284, 1805 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Mayford, M. & Kandel, E. R. Genetic approaches to memory storage . Trends Genet. 15, 463– 470 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Bliss, T. V. P. Goddard, G. V. & Rives, M. Reduction of long-term potentiation in the dentate gyrus of the rat following selective depletion of monoamines. J. Physiol. (Lond.) 334, 475–491 ( 1983).

    Article  CAS  Google Scholar 

  86. Stanton, P. K. & Sarvey, J. M. Blockade of norepinephrine induced long-lasting potentiation in the hippocampal dentate gyrus by an inhibitor of protein synthesis. Brain Res. 361, 276–283 (1985).

    Article  CAS  PubMed  Google Scholar 

  87. Hopkins, W. & Johnston, D. Noradrenergic enhancement of long-term potentiation of mossy fiber synapses in the hippocampus. J. Neurophysiol. 59, 667–687 ( 1988).

    Article  CAS  PubMed  Google Scholar 

  88. Frey, U., Schoeder, H. & Matthies, H. Dopaminergic antagonists prevent long-term maintenance of posttetanic LTP in the CA1 region of rat hippocampal slices. Brain Res. 552, 69–75 ( 1990).

    Article  Google Scholar 

  89. Frey, U., Matthies, H., Reymann, K. G. & Matthies, H. The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CA1 region in vitro. Neurosci. Lett. 29, 111–114 (1991).

    Article  Google Scholar 

  90. Huang, Y.-Y. & Kandel, E. R. D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus . Proc. Natl Acad. Sci. USA 92, 2446– 2450 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Swanso-Park, J. L. et al. A double dissociation with the hippocampus of dopamine D1/D5 receptor and β-adrenergic receptor contributions to the persistence of long-term potentiation. Neuroscience 92, 485–497 (1999).

    Article  Google Scholar 

  92. Bach, M. E. et al. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc. Natl Acad. Sci. USA 96, 5280– 5285 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Huang, Y.-Y. & Kandel, E. R. Modulation of both the early and the late phase of mossy fiber LTP by the activation of β-adrenergic receptors . Neuron 16, 611–617 (1996).Highlights the importance of heterosynaptic modulation in the late phase of hippocampal LTP.

    Article  CAS  PubMed  Google Scholar 

  94. Winder, D. G. et al. ERK plays a regulatory role in induction of LTP by theta frequency stimulation and its modulation by β-adrenergic receptors. Neuron 24, 715–726 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  95. Thomas, M. J., Moody, T. D., Makhinson, M. & O'Dell, T. J. Activity-dependent β-adrenergic modulation of low frequency stimulation induced LTP in the hippocampal CA1 region. Neuron 17 , 475–482 (1996).

    Article  CAS  PubMed  Google Scholar 

  96. Thomas, M. J., Watabe, A. M., Moody, T. D., Makhinson, M. & O'Dell, T. J. Postsynaptic complex spike bursting enables the induction of LTP by theta frequency synaptic stimulation. J. Neurosci. 18, 7118–7126 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Scatton, B., Simon, H., Lemoal, M. & Bischoff, S. Origin of dopaminergic innervation of the rat hippocampal formation. Neurosci. Lett. 18, 125–131 (1980).

    Article  CAS  PubMed  Google Scholar 

  98. Uprichard, D. C., Reisine, T. D., Mason, S. T., Fibiger, H. C. & Yamanura, H. I. Modulation of rat brain α- and β-adrenergic receptor population by lesion of dorsal noradrenergic bundle. Brain Res. 187, 143– 154 (1980).

    Article  CAS  Google Scholar 

  99. Kobayashi, Y. & Amaral, D. G. in Handbook of Chemical Neuroanatomy: The Hippocampal Formation and Perirhinal and Parahippocampal Cortices (eds Bjorklund, A. & Hökfelt, T.) 359 (Elsevier, Amsterdam, 1999).

    Google Scholar 

  100. Moore, R. Y. & Bloom, F. E. Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu. Rev. Sci. 2, 113–168 (1979).

    CAS  Google Scholar 

  101. Loy, R., Koziell, D. A., Lindsey, J. D. & Moore, R. Y. Noradrenergic innervation of the adult rat hippocampal formation. J. Comp. Neurol. 189, 699–710 (1980).

    Article  CAS  PubMed  Google Scholar 

  102. Oleskevich, S., Descarries, L. D. & Lacaile, J.-C. Quantified distribution of the noradrenergic innervation in the hippocampus of adult rat. J. Neurosci. 9, 3803–3815 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nicholas, A. P., Pieribone, V. A. & Hökfelt, T. Cellular localization of messenger RNA for β1 and β2 adrenergic receptors in rat brain: an in situ hybridization study. Neuroscience 56, 1023–1039 (1993).

    Article  CAS  PubMed  Google Scholar 

  104. Stanton, P. K. & Garvey, M. M. The effect of high-frequency electrical stimulation and norepinephrine on cyclic AMP levels in normal versus norepinephrine-depleted rat hippocampal slices. Brain Res. 358, 343–348 (1985).

    Article  CAS  PubMed  Google Scholar 

  105. Winder, D. G. & Conn, T. J. Activation of metabotropic glutamate receptors increase cAMP accumulation in hippocampus by potentiating responses to endogenous adenosine. J. Neurosci. 13, 38–44 ( 1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Whitton, P. S. Glutamatergic control over brain dopamine release in vivo and in vitro. Neurosci. Biobehav. Rev. 21, 481–488 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Carew, T. J., Hawkins, R. D. & Kandel, E. R. Differential classical conditioning of a defensive withdrawal reflex in Aplysia californica. Science 219, 397–400 (1983).

    Article  CAS  PubMed  Google Scholar 

  108. Hawkins, R. D., Abrams, T. W., Carew, T. J. & Kandel, E. R. A cellular mechanism of classical conditioning in Aplysia: Activity-dependent amplification of presynaptic facilitation. Science 219, 400–405 (1983).

    Article  CAS  PubMed  Google Scholar 

  109. Walters, E. T. & Byrne, J. H. Associative conditioning of single sensory neurons suggests a cellular mechanism for learning. Science 219, 405–408 ( 1983).

    Article  CAS  PubMed  Google Scholar 

  110. Walters, E. T. & Byrne, J. H. Long-term enhancement produced by activity-dependent modulation of Aplysia sensory neurons . J. Neurosci. 5, 662–672 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Byrne, J. H. Cellular analysis of associative learning. Physiol. Rev. 67, 329–339 (1987).

    Article  CAS  PubMed  Google Scholar 

  112. Antonov, I., Antonova, I. & Hawkins, R. D. Activity-dependent facilitation of monosynaptic sensory neuron-motor neuron PSPs contributes to classical conditioning of the Aplysia siphon-withdrawal reflex in a simplified preparation. Soc. Neurosci. Abstr. 25, 1129 ( 1999).

    Google Scholar 

  113. Abrams, T. W., Karl, K. A. & Kandel, E. R. Biochemical studies of stimulus convergence during classical conditioning in Aplysia: dual regulation of adenylate cyclase by calcium/calmodulin and transmitter. J. Neurosci. 11, 2655–2665 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lin, X. Y. & Glanzman, D. L. Hebbian induction of long-term potentiation of Aplysia sensorimotor synapses: partial requirement for activation of an NMDA-related receptor. Proc. R. Soc. Lond. B 255, 215–221 ( 1994).

    Article  CAS  Google Scholar 

  115. Murphy, G. G. & Glanzman, D. L. Mediation of classical conditioning in Aplysia californica by long-term potentiation of sensorimotor synapses. Science 278, 467 –470 (1997).

    Article  CAS  PubMed  Google Scholar 

  116. Bao, J.-X., Kandel, E. R. & Hawkins, R. D. Involvement of pre- and postsynaptic mechanisms in posttetanic potentiation at Aplysia synapses. Science 275, 969–973 (1997).

    Article  CAS  PubMed  Google Scholar 

  117. Bao, J.-X., Kandel, E. R. & Hawkins, R. D. Involvement of presynaptic and postsynaptic mechanisms in a cellular analog of classical conditioning at Aplysia sensory-motor neuron synapses in isolated cell culture. J. Neurosci. 18, 458–466 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Antonov, I., Kandel, E. R. & Hawkins, R. D. Contribution of pre- and postsynaptic mechanisms to activity-dependent facilitation during classical conditioning of the Aplysia siphon–withdrawal reflex. Soc. Neurosci. Abstr. (in the press).

  119. Bailey, C. H., Giustetto, M., Zhu, H., Chen, M. & Kandel, E. R. A novel function for 5-HT mediated short-term facilitation in Aplysia: conversion of a transient, cell-wide homosynaptic plasticity into a persistent, protein synthesis-independent synapse–specific enhancement . Proc. Natl Acad. Sci. USA (in the press).

  120. Schacher, S., Wu, F. & Sun, Z.-Y. Pathway-specific synaptic plasticity: activity-dependent enhancement and suppression of long-term heterosynaptic facilitation at converging inputs on a single target. J. Neurosci. 17, 597– 606 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sutton, M. A. & Carew, T. J. Parallel molecular pathways mediate expression of distinct forms of intermediate-term facilitation at tail sensory-motor synapses in Aplysia. Neuron 26, 219–231 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Crow, T. J. & Wendlandt, S. Impaired acquisition of a passive avoidance response after lesions induced in the locus coeruleus by 6-OH-dopamine . Nature 259, 42–44 (1976).

    Article  CAS  PubMed  Google Scholar 

  123. Gold, P. E. & Van Buskirk, R. Posttraining brain norepinephrine concentrations of avoidance training and with peripheral epinephrine modulation of memory processing. Behav. Biol. 23, 509 –520 (1978).

    Article  CAS  PubMed  Google Scholar 

  124. Castellano, C., Cestari, V., Cabib, S. & Puglisi-Allegra, S. Post-training dopamine receptor agonists and antagonists affects memory storage in mice irrespective of their selectivity for D1 and D2 receptors. Behav. Neural Biol. 3, 283–291 (1991).

    Article  Google Scholar 

  125. Montague, P. R. Integrating information at single synaptic connections. Proc. Natl Acad. Sci. USA 92, 2424–2425 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Roozendaal, B., Williams, C. L. & McGaugh, J. L. Glucocortioid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala. Eur. J. Neurosci. 4, 1317–1323 (1999).

    Article  Google Scholar 

  127. Morris, R. G. & Frey, U. Hippocampal synaptic plasticity: role in spatial learning or the automatic recording of attended experience? Phil. Trans. R. Soc. Lond. B 352, 1489–1503 (1997).

    Article  CAS  Google Scholar 

  128. LeDoux, J. E. Fear and the brain: where have we been, and where are we going? Biol. Psychiat. 44, 1229–1238 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Damasio, A. R. Descartes' Error: Emotion, Reason, and the Human Brain (Putnam's Sons, New York, 1995).

    Google Scholar 

  130. McGaugh, J. L. Memory — a century of consolidation. Science 287, 248–251 (2000). Reviews the importance of modulatory transmitters for attentional and motivational significance of long-term memory storage.

    Article  CAS  PubMed  Google Scholar 

  131. Bernabeu, R. et al. Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats. Proc. Natl Acad. Sci. USA 94, 7041–7046 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hersi, A. I., Rowe, W., Gaudreau, P. & Quirion, R. Dopamine D1 receptor ligands modulate cognitive performance and hippocampal acetylcholine release in memory-impaired aged rats. Neuroscience 69, 1067–1074 (1995).

    Article  CAS  PubMed  Google Scholar 

  133. Yin, J. C. & Tully, T. CREB and the formation of long-term memory. Curr. Opin. Neurobiol. 6, 264– 268 (1996).Review of the role of CREB in long-term memory storage.

    Article  CAS  PubMed  Google Scholar 

  134. Schultz, W., Dayan, P. & Montague, P. R. A. A neural substrate of prediction and reward. Science 275, 1593–1599 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  135. Schultz, W. & Dickinson, A. Neuronal coding of prediction errors. Annu. Rev. Neurosci. 23, 473– 500 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Wilson, F. A. & Rolls, E. T. Learning and memory is reflected in the responses of reinforcement-related neurons in the primate basal forebrain. J. Neurosci. 10, 1254–1267 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Frey, U. & Morris, R. G. Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 21, 181–188 ( 1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Tom Carew, John Koester, Kelsey Martin, James McGaugh, Tom O'Dell, Chris Pittenger, Steve Siegelbaum and Danny Winder for their comments on an earlier version of this manuscript. We thank Harriet Ayers and Millie Pellan for preparation of the manuscript and Charles Lam for assisting with the artwork. C.H.B. is supported by a National Institutes of Health grant. E.R.K. is supported by the Howard Hughes Medical Institute, the G. Harold and Leila Y. Mathers Charitable Foundation and the Lieber Centre for Schizophrenia Research. M.G. is supported by a Human Frontier Science Program Organization fellowship.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, 10032, New York, USA

    Craig H. Bailey, Maurizio Giustetto, Yan-You Huang, Robert D. Hawkins & Eric R. Kandel

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  1. Craig H. Bailey
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  2. Maurizio Giustetto
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Related links

Related links

DATABASE LINKS

Apylsia database project

FURTHER INFORMATION

Eric Kandel's laboratory homepage

ENCYCLOPEDIA OF LIFE SCIENCES

Long-term potentiation

Molluscan nervous systems

Heterosynaptic modulation of synaptic efficacy

Protein phosphorylation and long-term synaptic plasticity

Learning and memory

Glossary

SYNAPTIC PLASTICITY

A change in the functional properties of a synapse as a result of use.

SENSITIZATION

A strengthening of the response to a wide variety of neutral stimuli following an intense or noxious stimuli.

CLASSICAL CONDITIONING

Form of associative learning in which a subject learns the relationship between two stimuli.

HABITUATION

A decrease in the behavioural response to a repeated, benign stimulus.

LOCUS COERULEUS

Nucleus of the brainstem. The main supplier of noradrenaline to the brain.

DORSAL RAPHE

Nucleus of the brainstem. The main supplier of serotonin to the brain.

VENTRAL TEGMENTAL AREA

Nucleus of the midbrain. The main supplier of dopamine to the cortex.

STRATUM LUCIDUM

The site of termination of the hippocampal mossy fibres.

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Bailey, C., Giustetto, M., Huang, YY. et al. Is Heterosynaptic modulation essential for stabilizing hebbian plasiticity and memory. Nat Rev Neurosci 1, 11–20 (2000). https://doi.org/10.1038/35036191

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