Molecular Neurobiology

, Volume 10, Issue 2–3, pp 135–149 | Cite as

Regulation of neuropeptide expression in the brain by neurotrophins

Potential role in vivo
  • Josette Carnahan
  • Hiroyuki Nawa
Proceedings of the Satellite of the 14th ISN Meeting and the First International Workshop entitled The Neuronal Phenotype Molecular Biology, Cell Specification, and Therapeutic Frontiers held in Lozari, Corsica, France, August 19–20, 1993


Neurotrophins, which are structurally related to nerve growth factor, have been shown to promote survival of various neurons. Recently, we found a novel activity of a neurotrophin in the brain: Brain-derived neurotrophic factor (BDNF) enhances expression of various neuropeptides. The neuropeptide differentiation activity was then compared among neurotrophins both in vivo and in vitro. In cultured neocortical neurons, BDNF and neurotrophin-5 (NT-5) remarkably increased levels of neuropeptide Y and somatostatin, and neurotrophin-3 (NT-3) also increased these peptides but required higher concentrations. At elevating substance P, however, NT-3 was as potent as BDNF. In contrast, NGF had negligible or no effect. Neurotrophins administered into neonatal brain exhibited slightly different potencies for increasing these neuropeptides: The most marked increase in neuropeptide Y levels was obtained in the neocortex by NT-5, whereas in the striatum and hippocampus by BDNF, although all three neurotrophins increased somatostatin similarly in all the brain regions examined. Overall spatial patterns of the neuropeptide induction were similar among the neurotrophins. Neurons in adult rat brain can also react with the neurotrophins and alter neuropeptide expression in a slightly different fashion. Excitatory neuronal activity and hormones are known to change expression of neurotrophins. Therefore, neurotrophins, neuronal activity, and hormones influence each other and all regulate neurotransmitter/peptide expression in developing and mature brain. Physiological implication of the neurotransmitter/peptide differentiation activities is also discussed.

Index Entries

Nerve growth factor brain-derived neurotrophic factor neurotrophin, neuropeptide Y somatostatin substance P neocortex striatum hippocampus seizure plasticity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agoston D. V., Eiden L. E., and Brenneman D. E. (1991)J. Neurosci. Res. 28, 140.PubMedCrossRefGoogle Scholar
  2. Alderson R. F., Alterman A. L., Barde Y., and Lindsay R. M. (1990)Neuron 5, 297.PubMedCrossRefGoogle Scholar
  3. Baldino F., Fitzpatrick-McElligott S., O'Kane T. M., and Gozes I. (1988)Synapse 2, 317.PubMedCrossRefGoogle Scholar
  4. Bannon M. J., Elliott P. J., and Bunney E. B. (1987)Mol. Brain Res. 3, 31.CrossRefGoogle Scholar
  5. Barbany G. and Persson H. (1993)Neuroscience 54, 909.PubMedCrossRefGoogle Scholar
  6. Barbany G. and Persson H. (1992)Eur. J. Neurosci. 4, 396.PubMedCrossRefGoogle Scholar
  7. Barde Y. A., Edgar D.,and Thoenen H. (1982)EMBO J. 1, 549.PubMedGoogle Scholar
  8. Bazan J. F. (1991)Neuron 7, 197.PubMedCrossRefGoogle Scholar
  9. Bellmann R., Widmann R., Olenick C., Meyer D. K., Maas D., Marksteiner J., and Sperk G. (1991)J. Neurochem. 56, 525.PubMedCrossRefGoogle Scholar
  10. Barkemeier L. R., Winslow J. W., Kaplan D. R., Nikolics K., Goeddel D. V., and Rosenthal A. (1991)Neuron 7, 857.CrossRefGoogle Scholar
  11. Berzaghi M. P., Cooper J., Castren E., Zafra F., Sofroniew M., Thoenen H., and Lindholm D. (1993)J. Neurosci. 13, 3818.Google Scholar
  12. Bessho Y., Nakanishi S., and Nawa H. (1993)Mol. Brain Res. 18, 201.PubMedCrossRefGoogle Scholar
  13. Bugra K., Pollard H., Charton G., Moreau J., Ben-Ari Y., and Khrestchatisky M. (1994)Eur. J. Neurosci. 6, 58.PubMedCrossRefGoogle Scholar
  14. Castren E., Zafra F., Thoenen H., and Lindholm D. (1992)Proc. Natl. Acad. Sci. USA 89, 9444.PubMedCrossRefGoogle Scholar
  15. Castren E., Pitkänen M., Sirviö J., Parsadanian A., Lindholm D., Thoenen H., and Riekkinen P. J. (1993)Neuroreport 4, 895.PubMedCrossRefGoogle Scholar
  16. Cohen-Cory S., Dreyfus C. F., and Black I. B. (1991)J. Neurosci. 11, 462.PubMedGoogle Scholar
  17. Collazo E., Takahashi H., and McKay R. (1992)Neuron 9, 643.PubMedCrossRefGoogle Scholar
  18. Coulombe J. N., Schwall R., Parent A. S., Eckenstein F. P., and Nishi R. (1992)Neuron 10, 899.CrossRefGoogle Scholar
  19. Croll S. D., Wiegand S. J., Anderson K. D., Lindsay R. M., and Nawa H. (1993)Eur. J. Neurosci. 6, 1343.CrossRefGoogle Scholar
  20. Dugich-Djordjevic M. M., Tocco G., Willoughby D. A., Najm I., Pasinetti G., Thompson R. F., Baudry M., Lapchak P. A., and Hefti F. (1992)Neuron 8, 1127.PubMedCrossRefGoogle Scholar
  21. Ernfors P., Merlio J. P., and Persson H. (1992)Eur. J. Neurosci. 4, 1140.PubMedCrossRefGoogle Scholar
  22. Ernfors P., Lee K.-F., and Jaenisch R. (1994)Nature 368, 147.PubMedCrossRefGoogle Scholar
  23. Ernsberger U., Sendtner M., and Rohrer H. (1989)Neuron 2, 1275.PubMedCrossRefGoogle Scholar
  24. Fann M. and Patterson P. H. (1993)J. Neurochem. 61, 1349.PubMedCrossRefGoogle Scholar
  25. Freidin M. and Kessler J. A. (1991)Proc. Natl. Acad. Sci. USA 88, 3200.PubMedCrossRefGoogle Scholar
  26. Friedman W. J., Olson L., and Persson H. (1991a)Eur. J. Neurosci. 3, 688.PubMedCrossRefGoogle Scholar
  27. Friedman W. J., Ernfors P., and Persson H. (1991b)J. Neurosci. 11, 1577.PubMedGoogle Scholar
  28. Fukada K. (1980)Nature 287, 553.PubMedCrossRefGoogle Scholar
  29. Fukada K. (1985)Proc. Natl. Acad. Sci. USA 82, 8795.PubMedCrossRefGoogle Scholar
  30. Gall C. M. and Isackson P. J. (1989)Science 245, 758.PubMedCrossRefGoogle Scholar
  31. Gall C. M., Berschauer R., and Isackson P. J. (1994)Mol. Brain Res. 21, 190.PubMedCrossRefGoogle Scholar
  32. Gall C., Lauterborn J., Bundman M., Murray K., and Isackson P. (1991) InGenetic Strategies in Epilepsy Research (Anderson V. E., Hauser W. A., Leppik I. E., Noebels J. L., and Rich S. S., eds.), Elsevier, Amsterdam, p. 225.Google Scholar
  33. Gerfen C. R., McGinty J. F., and Young W. S. (1991)J. Neurosci. 11, 1061.Google Scholar
  34. Giordano T., Pan J. P., Casuto D., Watanabe S., and Arneric S. P. (1992)Mol. Brain Res. 16, 239.PubMedCrossRefGoogle Scholar
  35. Gotz R., Koster R., Winkler C., Rauls F., Lottspeich F., Schartl M., and Thoenen H. (1994)Nature 372, 266–269.PubMedCrossRefGoogle Scholar
  36. Greene L. A. and Tischler A. S. (1976)Proc. Natl. Acad. Sci. USA 73, 2424.PubMedCrossRefGoogle Scholar
  37. Habecker B. A. and Landis S. C. (1994)Science 264, 1602.PubMedCrossRefGoogle Scholar
  38. Halböök F., Ibáñez C. F., and Persson H. (1991)Neuron 6, 845.CrossRefGoogle Scholar
  39. Hatanaka H. and Tsukui H. (1986)Dev. Brain Res. 30, 47.CrossRefGoogle Scholar
  40. Hefti F., Hartikka J., Eckenstein F., Gnahn H., Heumann R., and Schwab M. (1985)Neuroscience 14, 55.PubMedCrossRefGoogle Scholar
  41. Hendry S. H. C., Jones E. G., and Burstein N. (1988)J. Neurosci. 8, 1225.PubMedGoogle Scholar
  42. Hohn A., Leibrock J., Bailey K. and Barde Y. A. (1990)Nature 344, 339.PubMedCrossRefGoogle Scholar
  43. Hyatt-Sachs H., Schreiber R. C., Bennett T. A., and Zigmond R. E. (1993)J. Neurosci. 13, 1642.PubMedGoogle Scholar
  44. Hyman C., Juhasz M., Jackson C., Wright P., Ip N. Y., and Lindsay R. M. (1994)J. Neurosci. 14, 335.PubMedGoogle Scholar
  45. Hyman C., Hofer M., Barde Y.-A., Juhasz M., Yancopoulos G. D., Squinto S. P., and Lindsay R. M. (1991)Nature 350, 230.PubMedCrossRefGoogle Scholar
  46. Illes P. and Regenold J. T. (1990)Nature 344, 62.PubMedCrossRefGoogle Scholar
  47. Ip N. Y., Li, Y., Yancopoulos G. D., and Lindsay R. M. (1993)J. Neurosci. 13, 3394.PubMedGoogle Scholar
  48. Isackson P. J., Huntsman M. M., Murray K. D., and Gall C. M. (1991)Neuron 6, 937.PubMedCrossRefGoogle Scholar
  49. Jacquin T., Champagnat J., Madamba S., Denavit-Saubie M., and Siggins G. R. (1985)Proc. Natl. Acad. Sci. USA 85, 948.CrossRefGoogle Scholar
  50. Jonakait G. M. and Schotland S. (1990)J. Neurosci. Res. 26, 24.PubMedCrossRefGoogle Scholar
  51. Jones K. R., Farinas I., Backus C., and Reichardt L. F. (1994)Cell 76, 989.PubMedCrossRefGoogle Scholar
  52. Kasper S., Popescu R. A., Torsello A., Vrontakis M. E., Ikejiani C., and Friesen H. G. (1992)Endocrinology 130, 1796.PubMedCrossRefGoogle Scholar
  53. Klein R., Conway D., Parada L. F., and Barbacid M. (1990)Cell 61, 647.PubMedCrossRefGoogle Scholar
  54. Krnjevic K. (1975)Physiol. Rev. 54, 418.Google Scholar
  55. Knüsel B., Beck K. D., Winslow J. W.,Rosenthal A., Burton L. E., Widmer H. R., Nikolics K., and Hefti F. (1992)J. Neurosci. 12, 4391.PubMedGoogle Scholar
  56. Knüsel B., Rabin S. J., Hefti F., and Kaplan D. R. (1994)J. Neurosci. 14, 1542.PubMedGoogle Scholar
  57. Kowall N. W. and Beal M. F. (1998)Ann. Neurol. 23, 105.CrossRefGoogle Scholar
  58. Lamballe F., Smeyne R. J., and Barbacid M. (1994J. Neurosci. 14, 14.PubMedGoogle Scholar
  59. Leibrock J., Lottspeich F., Hohn A., Hofer M., Hengerer B., Masiakowski P., Thoenen H., and Barde Y.-A. (1989)Nature 341, 149.PubMedCrossRefGoogle Scholar
  60. Levi-Montalcini R. (1987)EMBO J. 6, 1145.PubMedGoogle Scholar
  61. Lindefors, N., Brodin K., Stiller C. O., Persson H., and Brodin E. (1991)Neuroscience 45, 73.PubMedCrossRefGoogle Scholar
  62. Lindholm D., Castren E., Hengerer B., Zafra F., Beminger B., and Thoenen H. (1992)Eur. J. Neurosci. 4, 404.PubMedCrossRefGoogle Scholar
  63. Lindholm D., Castren E., Tsoulfas P., Kolbeck R., Berzaghi M. P., Leingartner A., Heisenberg C. P., Tesarollo L., Parada L. F., and Thoenen H. (1993)J. Cell Biol. 122, 443.PubMedCrossRefGoogle Scholar
  64. Lindholm D., Dechant G., Heisenberg C.-P., and Thoenen H. (1993)Eur. J. Neurosci. 5, 1455.PubMedCrossRefGoogle Scholar
  65. Lindsay R. M. and Harmar A. J. (1989)Nature 337, 362.PubMedCrossRefGoogle Scholar
  66. Lindsay R. M. (1988)J. Neurosci. 8, 2394.PubMedGoogle Scholar
  67. Lu B., Yokoyama M., Dreyfus C. F., and Black I. B. (1991)Proc. Natl. Acad. Sci. USA 88, 6289.PubMedCrossRefGoogle Scholar
  68. Maisonpierre P. C., Belluscio L., Friedman B., Alderson R. F., Wiegand S. J., Furth M. E., Lindsay R. M., and Yancopoulos G. D. (1990)Neuron 5, 501.PubMedCrossRefGoogle Scholar
  69. Maisonpierre P. C., Belluscio L., Squinto S., Ip N. Y., Furth M. E., Lindsay R. M., and Yancopoulos G. D. (1990)Science 247, 1446.PubMedCrossRefGoogle Scholar
  70. Marksteiner J. and Sperk G. (1988)Neuroscience 26, 379.PubMedCrossRefGoogle Scholar
  71. Martinez H. J., Dreyfus C. F., Jonakait G. M. and Black I. B. (1985)Proc. Natl. Acad. Sci. USA 82, 7777.PubMedCrossRefGoogle Scholar
  72. Martinou J., Martinou I., and Kato A. C. (1992)Neuron 8, 737.PubMedCrossRefGoogle Scholar
  73. McQuiston A. R. and Colmers W. F. (1993)Soc. Neurosci. Abstr. 19, 625.2.Google Scholar
  74. Mizuno K., Carnahan J., and Nawa H. (1994)Dev. Biol. 165, 243.PubMedCrossRefGoogle Scholar
  75. Moore S. D., Madamba S. G., Joels M., and Siggins G. R. (1988)Science 239, 278.PubMedCrossRefGoogle Scholar
  76. Murrison J. H., Rogers J., Scherr S., Benoit R., and Bloom F. E. (1985)Nature 314, 90.CrossRefGoogle Scholar
  77. Murphy M., Reid K., Hilton D. J., and Bartlett P. F. (1991)Proc. Natl. Acad. Sci. USA 88, 3498.PubMedCrossRefGoogle Scholar
  78. Nawa H. and Sah D. W. Y. (1990)Neuron 4, 279.PubMedCrossRefGoogle Scholar
  79. Nawa H., Bessho Y., Carnahan J., Nakanishi S., and Mizuno K. (1993)J. Neurochem. 60, 772.PubMedCrossRefGoogle Scholar
  80. Nawa H., Pelleymounter M. A., and Carnahan J. (1994)J. Neurosci. 14, 3751.PubMedGoogle Scholar
  81. Nawa H., Yamamori Y., Le T., and Patterson P. H. (1990)Cold Spring Harbor Symp. Quant. Biol. 55, 247.PubMedGoogle Scholar
  82. Nawa H., Carnahan J., and Gall C. (1995)Eur. J. Neurosci., in press.Google Scholar
  83. Olenik C., Meyer D. K., Marksteiner J., and Sperk G. (1989)Synapse 4, 223.PubMedCrossRefGoogle Scholar
  84. Patterson P. H. and Nawa H. (1993)Cell 72/Neuron 10, Suppl.), 123.CrossRefGoogle Scholar
  85. Patterson S. L., Grover L. M., Schwartzkroin P. A., and Bothwell M. (1992)Neuron 9, 1081PubMedCrossRefGoogle Scholar
  86. Phillips H. S., Hains J. M., Armanini M., Laramee G. R., Johnson S. A., and Winslow J. W. (1991)Neuron 7, 695.PubMedCrossRefGoogle Scholar
  87. Rao M. S., Symes A., Malik N., Shoyab M., Fink J. S., and Landis S. C. (1992)Neuroreport 3, 865.PubMedCrossRefGoogle Scholar
  88. Rao M. S., Tyrrell S., Landis S. C., and Patterson P. H. (1992)Dev. Biol. 150, 281.PubMedCrossRefGoogle Scholar
  89. Ringstedt T., Lagercrantz H., and Persson H. (1993)Dev. Brain Res. 72, 119.CrossRefGoogle Scholar
  90. Saadat S., Sendtner M., and Rohrer H. (1989)J. Cell Biol. 108, 1807.PubMedCrossRefGoogle Scholar
  91. Shadiack A. M., Hart R. P., and Jonakait G. M. (1992)Soc. Neurosci. Abstr. 22, 547.4.Google Scholar
  92. Simerly R. B. and Swanson L. W. (1987)Proc. Natl. Acad. Sci. USA 84, 2087.PubMedCrossRefGoogle Scholar
  93. Simerly R. B., Young B. J., Capozza M. A., and Swanson L. W. (1989)Proc. Natl. Acad. Sci. USA 86, 4766.PubMedCrossRefGoogle Scholar
  94. Smeyne R. J., Klein R., Schnapp A., Long L. K., Bryant S., Lewin A., Lira A., and Barbacid M. (1994)Nature 368, 264.CrossRefGoogle Scholar
  95. Smith M. A., Makino S., Kvetnansky R., and Post R. M. (1993a)Soc. Neurosci. Abstr. 19, 358.6.Google Scholar
  96. Smith M. A., Makino S., Kvetnansky R., and Post R. M. (1993b)Soc. Neurosci. Abstr. 19, 358.6.Google Scholar
  97. Soppet D., Escandon E., Maragos J., Middlemas D. S., Reis S. W., Blair J., Burton L. E., Stanton B. R., Kaplan D. R., Hunter T., Nikolics K., and Parada L. F. (1991)Cell 65, 895.PubMedCrossRefGoogle Scholar
  98. Sperk G., Wieser R., Widmann R., and Singer E. A. (1986)Neuroscience 17, 1117.PubMedCrossRefGoogle Scholar
  99. Tempel A., Kessler J. A., and Zukin R. S. (1990)J. Neurosci. 10, 741.PubMedGoogle Scholar
  100. Timmusk T., Belluardo N., Metsis M., and Persson H. (1993)Eur. J. Neurosci. 5, 605.PubMedCrossRefGoogle Scholar
  101. Tolon R. M., Franco F. S., de los Frailes M. T., Lorenzo M. J., and Cacicedo L. (1994)J. Neurosci. 14, 1053.PubMedGoogle Scholar
  102. Tsoulfas P., Soppet D., Escandon E., Tessarollo L., Mendoza-Ramirez J., Rosenthal A., Nikolics K., and Parada L. F. (1993)Neuron 10, 975.PubMedCrossRefGoogle Scholar
  103. Valuenzuela D. M., Maisonpierre P. C., Glass D. J., Rojas E., Nunez L., Kong Y., Gles R. R., Stitt T. N., Ip N. Y., and Yancopoulos G. D. (1993)Neuron 10, 963.CrossRefGoogle Scholar
  104. Wahlestedt C., Karoum F., Jaskiw G., Wyatt R. J., Larhammar D., Ekman R., and Reis D. (1991)Proc. Natl. Acad. Sci. USA 88, 2078.PubMedCrossRefGoogle Scholar
  105. Yamamori T., Fukada K., Aebersold R., Korsching S., Fann M., and Patterson P. H. (1989)Science 246, 1412.PubMedCrossRefGoogle Scholar
  106. Zafra F., Castren E., Thoenen H., and Lindholm D. (1991)Proc. Natl. Acad. Sci. USA 88, 10,037.CrossRefGoogle Scholar
  107. Zafra F., Hengerer B., Leibrock J., Thoenen H., and Lindholm D. (1990)EMBO J. 9, 3545.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 1995

Authors and Affiliations

  • Josette Carnahan
    • 1
  • Hiroyuki Nawa
    • 2
  1. 1.Amgen CenterNeuroscience DivisionThousand Oaks
  2. 2.Beckman Neuroscience CenterCold Spring Harbor LaboratoryCold Spring Harbor

Personalised recommendations