Protein F1 and Protein Kinase C May Regulate the Persistence, Not the Initiation, of Synaptic Potentiation in the Hippocampus

  • David M. Lovinger
  • Aryeh Routtenberg
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 221)


Brain information storage likely involves enhanced neuronal responsiveness which persists for long periods of time following learning. Hebb (1949) first postulated a mechanism for such enhanced responsiveness in which repetitive activation of a synapse would produce persistent increases in the efficacy of transmission at that synapse.


High Frequency Stimulation Perforant Path Synaptic Efficacy Spike Amplitude Synaptic Potentiation 
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  1. Akers, R. F. and Routtenberg, A., Kinase C phosphorylates a protein involved in synaptic plasticity, Br. Res. 334:147–151 (1985).CrossRefGoogle Scholar
  2. Akers, R. F., Lovinger, D., Colley, P., Linden, D. and Routtenberg, A., Translocation of protein kinase C activity may mediate hippocampal long term potentiation, Science 231:587–589 (1986).CrossRefGoogle Scholar
  3. Aloyo, V. J., Zwiers, H. and Gispen, W. H., Phosphorylation of B-50 protein by calcium-activated, phospholipid-dependent protein kinase and B-50 protein kinase, J. Neurochem. 41:649–653 (1983).CrossRefGoogle Scholar
  4. Andersen, P., Bliss, T. V. P. and Skrede, K. K., Lamellar organization of hippocampal excitatory pathways, Exp. Br. Res. 13:222–238 (1971).Google Scholar
  5. Barnes, C. A., Memory deficits associated with senescence: A behavioral and electrophysiological study, J. Comp. Physiol. Psychol., 93:74–104 (1979).CrossRefGoogle Scholar
  6. Barnes, C. A. and McNaughton, B. L., Spatial memory and hippocampal synaptic plasticity in senescent and middle-aged rats. In D. G. Stein (ed.), The Psychobiology of Aging: Problems and Perspectives, Elsevier/Holland, Amsterdam 253–272 (1980).Google Scholar
  7. Berger, T. W., Long-term potentiation of hippocampal synaptic transmission affects rate of behavioral learning, Science, 224:627–630 (1984).CrossRefGoogle Scholar
  8. Berridge, M. J., Rapid accumulation of inositol triphosphate reveals that agonists hydrolyse polyphosphoinositides instead of phosphatidylinositol, Biochem. J. 212:849–858 (1983).Google Scholar
  9. Bliss, T. V. P. and Lomo, T., Long lasting potentiation of synaptic transmission in the dentate area of the anesthetized rabbit following stimulation of the perforant path, J. Physiol., 232: 331–356 (1973).Google Scholar
  10. Cain, S. and Routtenberg, A., Neonatal handling selectively alters the phosphorylation of a 47,000 mol. wt. protein in male rat hippocampus, Br. Res. 267: 192–195 (1983).CrossRefGoogle Scholar
  11. Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U. and Nishizuka, Y., Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters, J. Biol. Chem., 257: 7847–7851 (1982).Google Scholar
  12. Chan, S. Y., Murakami, K. and Routtenberg, A., Purification of a kinase C substrate: brain phosphoprotein F1 and the discovery of an endogenous kinase C inhibitory factor, Soc. Neurosci. Abstr., 11: 926 (1985).Google Scholar
  13. Collingridge, G. L., Long term potentiation in the hippocampus: mechanisms of initiation and modulation by neurotransmitters, Trends in Pharm. Sci., 6: 407–411 (1985).CrossRefGoogle Scholar
  14. Delorenzo, R. J., Calcium, calmodulin. and synaptic function: Modulators of neurotransmitter release, nerve terminal protein phosphorylation and synaptic vesicle morphology by calcium and calmodulin, In: R. Tapia and C. W. Cotman (eds.), Regulatory Mechanisms of Synaptic Transmission, Plenum Press, New York, 205–240 (1981).CrossRefGoogle Scholar
  15. Desmond, N. and Levy, W. B., Synaptic correlates of associative potentiation/depression: An ultrastructural study in the hippocampus, Br. Res. 265 (1): 21–30 (1983).CrossRefGoogle Scholar
  16. Douglas, R. M. and Goddard, G. V., Long-term potentiation of the perforant path-granule cell synapse in the rat hippocampus, Br. Res. 86: 205–215 (1975).CrossRefGoogle Scholar
  17. Ehrlich, Y. H., Rabjohns, R. R. and Routtenberg, A., Experiental-input alters the phosphorylation of specific proteins in brain membranes, Pharm. Biochem. Behav., 6: 354–360 (1977).CrossRefGoogle Scholar
  18. Hebb, D. O., The Organization of Behavior, John Wiley and Sons, New York (1949).Google Scholar
  19. Hjorth-Simonsen, A., Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentata, J. Comp. Neurol., 146: 219–232 (1972).CrossRefGoogle Scholar
  20. Kraft, A. S. and Andersen, W. B., Phorbol esters increase the amount of Ca2+, phospholipid-dependent protein kinase associated with the plasma membrane, Nature, 301: 621 (1983).CrossRefGoogle Scholar
  21. Lee, K. S., Schottler, F., Oliver, M. and Lynch, G., Brief bursts of highfrequency stimulation produce two types of structural change in rat hippocampus, J. Neurophysiol., 44: 247–258 (1980).Google Scholar
  22. Linden, D. J., Murakami, K. and Routtenberg, A., A newly discovered protein kinase C activator (oleic acid) enhances long-term potentiation in the intact hippocampus, Br. Res., 379: 358–363 (1986).CrossRefGoogle Scholar
  23. Linden, D. J., Murakami, K. and Routtenberg, A., Oleic acid, a protein kinase C activator, enhances hippocampal long-term potentiation, Soc.Neurosci. Abstr., 12: 1169 (1986).Google Scholar
  24. Lomo, T., Patterns of activation in a monosynaptic cortical pathway: The perforant path input to the dentate area of the hippocampal formation, Exp. Br. Res., 12: 18–45 (1971).Google Scholar
  25. Lovinger, D., Colley, P., Linden, D., Mukarami, K. and Routtenberg, A., Phorbol ester, which induces protein kinase C (PKC) translocation to the membrane, prevents decay of long term potentiation, Soc. Neurosci. Abstr., 11: 927 (1985).Google Scholar
  26. Lovinger, D. M., Akers, R. F., Nelson, R. B., Barnes, C. A., McNaughton, B. L. and Routtenberg, A., A selective increase in the phosphorylation of protein Fl, a protein kinase C substrate, directly related to three day growth of long term synaptic enhancement, Br. Res., 343: 137–143 (1985).CrossRefGoogle Scholar
  27. Lovinger, D. M., Colley, P., Akers, R. F., Nelson, R. B. and Routtenberg, A., Direct relation of long-duration synaptic potentiation to phosphorylation of membrane protein F1: A substrate for membrane protein kinase C, Br, Res., in press (1986).Google Scholar
  28. Lovinger, D., Barnes, C. A., Mizumori, S. J. Y., Chan, S. Y., Linden, D., Murakami, K., Sheu, F-S. and Routtenberg, A., Protein F1, previously related to synaptic plasticity, exhibits decreased phosphorylation in senescent rat hippocampus, Soc. Neurosci., 12: 1168 (1986).Google Scholar
  29. Lowry, O. H., Rosebrough, N. J., Farr, A. L. and Randall, R. J., Protein measurement with the Folin phenol reagent, J. Biol. Chem., 193: 265–275 (1951).Google Scholar
  30. Lynch, G., Larson, J., Kelso, S., Barrioneuvo, G. and Schottler, F., Intracellular injections of EGTA block induction of hippocampal long-term potentiation, Nature, 305: 719–721 (1984).CrossRefGoogle Scholar
  31. McNaughton, B. L., Long-term synaptic enhancement and short-term potentiation in rat fascia dentata act through different mechanisms, J. Physiol., 324: 249–262 (1982).Google Scholar
  32. McNaughton, B. L., Barnes, C. A., Rao, G., Baldwin, J. and Rasmussen, M., Long-term enhancement of hippocampal synaptic transmission and the acquisition of spatial information, J. Neurosci., 6(2): 563–571 (1986).Google Scholar
  33. Morris, M. E., Krnjevic, K. and Ropert, N., Changes in free Ca++ recorded inside hippocampal neurons in response to fimbrial stimulation, Soc. Neurosci. Abstr., 9: 395 (1983).Google Scholar
  34. Morris, M. E., Krnjevic, K. and McDonald, J. F., Changes in intracellular free Ca ion concentration evoked by electrical activity in cat spinal neurons in situ, Neurosci., 14: 563–580 (1985).CrossRefGoogle Scholar
  35. Murakami, K. and Routtenberg, A., Direct activation of purified protein kinase C by the unsaturated fatty acids (oleate and arachidonate) in the absence of phospholipids and Ca2+, FEBS LETT., 192(2): 189–193 (1985).CrossRefGoogle Scholar
  36. Nelson, R. B. and Routtenberg, A., Characterization of the 47kD protein F1 (pI 4.5), a kinase C substrate directly related to neural plasticity, Exper. Neurol., 89: 213–224 (1985).CrossRefGoogle Scholar
  37. Nelson, R. B., Routtenberg, A., Hyman, C. and Pfenninger, K. H., A phosphoprotein, F1, directly related to neuronal plasticity in adult rat brain may be identical to a major growth cone membrane protein, Soc. Neurosci. Abstr., 11: 927 (1985).Google Scholar
  38. Nestler, E. J. and Greengard, P., Protein Phosphorylation in the Nervous System, John Wiley and Sons, New York (1984).Google Scholar
  39. Oestreicher, A. B., Zwiers, H., Schotman, P. and Gispen, W. H., Immunohistochemical localization of a phosphoprotein (B-50) isolated from rat brain synaptosomal plasma membranes, Brain Res. Bull., 6: 145–153 (1981).CrossRefGoogle Scholar
  40. Ranck, J. B., Studies on single neurons in dorsal hippocampal formation and septum in unrestrained rats, Part I. Behavioral correlates and firing repertoires, Exp. Neurol. 461–555 (1973).Google Scholar
  41. Rodnight, R., Aspects of protein phosphorylation in the nervous system with particular reference to synaptic transmission, In W. H. Gispen and A. Routtenberg (eds.), Prog. Br. Res. Vol. 56, Elsevier/Holland, Amsterdam, 1–25 (1982).Google Scholar
  42. Routtenberg, A., Anatomical localization of phosphoprotein and glycoprotein substrates of memory, Progr. Neurobiol., 12: 85–113 (1979).CrossRefGoogle Scholar
  43. Routtenberg, A., Memory formation as a post-translational modification of brain proteins. In: C.A. Marsan and H. Matthies (eds.), Mechanisms and Models of Neural Plasticity. Proc. VIth Intl. Neurobiol. IBRO Symposium on Learning and Memory, Raven Press, New York, pp. 17–24 (1982a).Google Scholar
  44. Routtenberg, A., Identification and back-titration of brain pyruvate dehydrogenase. In W. H. Gispen and A. Routtenberg (eds.), Prog. Brain Res. Vol. 56, Elsevier/Holland, Amsterdam, pp. 349–374 (1982b).Google Scholar
  45. Routtenberg, A., Brain phosphoproteins, Kinase C and Protein F1 protagonists of plasticity in particular pathways. In G. Lynch, J. McGaugh, and N. Weinberger (eds.), Neurobiology of Learning and Memory, The Guilford Press, New York, 479–490 (1984).Google Scholar
  46. Routtenberg, A., Synaptic plasticity and protein kinase C., In: W. H. Gispen and A. Routtenberg (eds.), Phosphoproteins in the Nervous System, Elsevier/Holland, Amsterdam, 211–234 (1986).CrossRefGoogle Scholar
  47. Routtenberg, A., Lovinger, D. and Steward O., Selective increase in the phosphorylation of a 47kD protein (F1) directly related to long-term potentiation, Behav. Neural Biol. 43: 3–11 (1985a).CrossRefGoogle Scholar
  48. Routtenberg, A., Protein kinase C activation leading to protein F1 phosphorylation may regulate synaptic plasticity by presynaptic terminal growth, Behav. Neural Biol., 44(2): 186–200 (1985b).CrossRefGoogle Scholar
  49. Routtenberg, A., Ehrlich, Y. H. and Rabjohns, R., Effect of a training experience on phosphorylation of a specific protein in neocortical and subcortical membrane preparations, Fed. Proc, 34: 293 (1975).Google Scholar
  50. Routtenberg, A., Colley, P., Linden, D., Lovinger, D., Murakami, K. and Sheu, F.-S., Phorbol ester promotes growth of synaptic plasticity, Br. Res. 378: 374–378 (1986).CrossRefGoogle Scholar
  51. Schwartzkroin, P. A. and Wester, K., Long-lasting facilitation of synaptic potential following tetanization in the hippocampal slice, Br. Res., 89: 107–119 (1975).CrossRefGoogle Scholar
  52. Snipes, G. J., Freeman, J. A., Costello, B., Chan, S. and Routtenberg, A., Evidence that the growth-associated protein, GAP-43, and plasticityassociated protein, protein F1, are identical, Soc. Neurosci. Abstr., 12 (1986).Google Scholar
  53. Takai, Y., Yamamoto, M., Inoue, M., Kishimoto, A. and Nishizuka, Y., A proenzyme of cyclic nucleotide independent protein kinase and its activation by calcium-dependent neutral protease from rat liver, Biochem. Biophys. Res. Comm., 77: 542–550 (1977).CrossRefGoogle Scholar
  54. Teyler, T. J. and Discenna, P., Long-term potentiation as a candidate mnemonic device, Br. Res. Rev., 7: 15–28 (1984).CrossRefGoogle Scholar
  55. Turner, R. W., Baimbridge, K. G. and Miller, J. J., Calcium-induced longterm potentiation in the hippocampus, Neurosci., 7: 1411–1416 (1982).CrossRefGoogle Scholar
  56. Van Harreveld, A. and Fifkova, E., Swelling of dendritic spines in the fascia dentata after stimulation of the perforant fibers as a mechanism of post-tetanotic potentiation, Exp. Neurol., 49: 736–739 (1975).CrossRefGoogle Scholar
  57. Zwiers, H., Jolles, J., Aloyo, V. J., Oestreicher, A. B. and Gispen, W. H., ACTH and synaptic membrane phosphorylation in rat brain, In: W. H. Gispen and A. Routtenberg (eds.), Prog. Br. Res., Vol. 56, Elsevier/ Holland, Amsterdam, 405–417 (1982).Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • David M. Lovinger
    • 1
  • Aryeh Routtenberg
    • 1
  1. 1.Cresap Neuroscience LaboratoryNorthwestern UniversityEvanstonUSA

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