Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Nov 15;88(22):10037–10041. doi: 10.1073/pnas.88.22.10037

Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons.

F Zafra 1, E Castrén 1, H Thoenen 1, D Lindholm 1
PMCID: PMC52862  PMID: 1658793

Abstract

In the central nervous system brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are predominantly located in neurons. Here we demonstrate that the balance between the activity of the glutamatergic and gamma-aminobutyric acid (GABA)ergic systems controls the physiological levels of BDNF and NGF mRNAs in hippocampal neurons in vitro and in vivo. The blockade of the glutamate receptors and/or stimulation of the GABAergic system reduces BDNF and NGF mRNAs in hippocampus and NGF protein in hippocampus and septum. The reduction of NGF in the septum reflects the diminished availability of NGF in the projection field of NGF-dependent septal cholinergic neurons. These neurons do not synthesize NGF themselves but accumulate it by retrograde axonal transport. The refined and rapid regulation of BDNF and NGF synthesis by the glutamate and GABA transmitter systems suggests that BDNF and NGF might be involved in activity-dependent synaptic plasticity.

Full text

PDF
10038

Images in this article

10040Image
on p.10040
10040Image
on p.10040

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alderson R. F., Alterman A. L., Barde Y. A., Lindsay R. M. Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron. 1990 Sep;5(3):297–306. doi: 10.1016/0896-6273(90)90166-d. [DOI] [PubMed] [Google Scholar]
  2. Artola A., Singer W. Long-term potentiation and NMDA receptors in rat visual cortex. Nature. 1987 Dec 17;330(6149):649–652. doi: 10.1038/330649a0. [DOI] [PubMed] [Google Scholar]
  3. Ayer-LeLievre C., Olson L., Ebendal T., Seiger A., Persson H. Expression of the beta-nerve growth factor gene in hippocampal neurons. Science. 1988 Jun 3;240(4857):1339–1341. doi: 10.1126/science.2897715. [DOI] [PubMed] [Google Scholar]
  4. Bandtlow C. E., Meyer M., Lindholm D., Spranger M., Heumann R., Thoenen H. Regional and cellular codistribution of interleukin 1 beta and nerve growth factor mRNA in the adult rat brain: possible relationship to the regulation of nerve growth factor synthesis. J Cell Biol. 1990 Oct;111(4):1701–1711. doi: 10.1083/jcb.111.4.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barth E. M., Korsching S., Thoenen H. Regulation of nerve growth factor synthesis and release in organ cultures of rat iris. J Cell Biol. 1984 Sep;99(3):839–843. doi: 10.1083/jcb.99.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brewer G. J., Cotman C. W. Survival and growth of hippocampal neurons in defined medium at low density: advantages of a sandwich culture technique or low oxygen. Brain Res. 1989 Aug 7;494(1):65–74. doi: 10.1016/0006-8993(89)90144-3. [DOI] [PubMed] [Google Scholar]
  7. Choi D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988 Oct;1(8):623–634. doi: 10.1016/0896-6273(88)90162-6. [DOI] [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Collingridge G. L., Singer W. Excitatory amino acid receptors and synaptic plasticity. Trends Pharmacol Sci. 1990 Jul;11(7):290–296. doi: 10.1016/0165-6147(90)90011-v. [DOI] [PubMed] [Google Scholar]
  10. Ferkany J. W., Zaczek R., Coyle J. T. Kainic acid stimulates excitatory amino acid neurotransmitter release at presynaptic receptors. Nature. 1982 Aug 19;298(5876):757–759. doi: 10.1038/298757a0. [DOI] [PubMed] [Google Scholar]
  11. Gall C. M., Isackson P. J. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science. 1989 Aug 18;245(4919):758–761. doi: 10.1126/science.2549634. [DOI] [PubMed] [Google Scholar]
  12. Gall C., Murray K., Isackson P. J. Kainic acid-induced seizures stimulate increased expression of nerve growth factor mRNA in rat hippocampus. Brain Res Mol Brain Res. 1991 Jan;9(1-2):113–123. doi: 10.1016/0169-328x(91)90136-l. [DOI] [PubMed] [Google Scholar]
  13. Gnahn H., Hefti F., Heumann R., Schwab M. E., Thoenen H. NGF-mediated increase of choline acetyltransferase (ChAT) in the neonatal rat forebrain: evidence for a physiological role of NGF in the brain? Brain Res. 1983 Jul;285(1):45–52. doi: 10.1016/0165-3806(83)90107-4. [DOI] [PubMed] [Google Scholar]
  14. Hefti F. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci. 1986 Aug;6(8):2155–2162. doi: 10.1523/JNEUROSCI.06-08-02155.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hempstead B. L., Martin-Zanca D., Kaplan D. R., Parada L. F., Chao M. V. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678–683. doi: 10.1038/350678a0. [DOI] [PubMed] [Google Scholar]
  16. Hofer M., Pagliusi S. R., Hohn A., Leibrock J., Barde Y. A. Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J. 1990 Aug;9(8):2459–2464. doi: 10.1002/j.1460-2075.1990.tb07423.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Honegger P., Lenoir D. Nerve growth factor (NGF) stimulation of cholinergic telencephalic neurons in aggregating cell cultures. Brain Res. 1982 Feb;255(2):229–238. doi: 10.1016/0165-3806(82)90023-2. [DOI] [PubMed] [Google Scholar]
  18. Kaplan D. R., Martin-Zanca D., Parada L. F. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature. 1991 Mar 14;350(6314):158–160. doi: 10.1038/350158a0. [DOI] [PubMed] [Google Scholar]
  19. Keinänen K., Wisden W., Sommer B., Werner P., Herb A., Verdoorn T. A., Sakmann B., Seeburg P. H. A family of AMPA-selective glutamate receptors. Science. 1990 Aug 3;249(4968):556–560. doi: 10.1126/science.2166337. [DOI] [PubMed] [Google Scholar]
  20. Klein R., Jing S. Q., Nanduri V., O'Rourke E., Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189–197. doi: 10.1016/0092-8674(91)90419-y. [DOI] [PubMed] [Google Scholar]
  21. Klein R., Martin-Zanca D., Barbacid M., Parada L. F. Expression of the tyrosine kinase receptor gene trkB is confined to the murine embryonic and adult nervous system. Development. 1990 Aug;109(4):845–850. doi: 10.1242/dev.109.4.845. [DOI] [PubMed] [Google Scholar]
  22. Knüsel B., Winslow J. W., Rosenthal A., Burton L. E., Seid D. P., Nikolics K., Hefti F. Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin 3. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):961–965. doi: 10.1073/pnas.88.3.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Korsching S., Thoenen H. Nerve growth factor in sympathetic ganglia and corresponding target organs of the rat: correlation with density of sympathetic innervation. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3513–3516. doi: 10.1073/pnas.80.11.3513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Leibrock J., Lottspeich F., Hohn A., Hofer M., Hengerer B., Masiakowski P., Thoenen H., Barde Y. A. Molecular cloning and expression of brain-derived neurotrophic factor. Nature. 1989 Sep 14;341(6238):149–152. doi: 10.1038/341149a0. [DOI] [PubMed] [Google Scholar]
  25. Lindholm D., Heumann R., Meyer M., Thoenen H. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature. 1987 Dec 17;330(6149):658–659. doi: 10.1038/330658a0. [DOI] [PubMed] [Google Scholar]
  26. Malherbe P., Sigel E., Baur R., Persohn E., Richards J. G., Mohler H. Functional characteristics and sites of gene expression of the alpha 1, beta 1, gamma 2-isoform of the rat GABAA receptor. J Neurosci. 1990 Jul;10(7):2330–2337. doi: 10.1523/JNEUROSCI.10-07-02330.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Monaghan D. T., Bridges R. J., Cotman C. W. The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol. 1989;29:365–402. doi: 10.1146/annurev.pa.29.040189.002053. [DOI] [PubMed] [Google Scholar]
  28. Phillips H. S., Hains J. M., Laramee G. R., Rosenthal A., Winslow J. W. Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons. Science. 1990 Oct 12;250(4978):290–294. doi: 10.1126/science.1688328. [DOI] [PubMed] [Google Scholar]
  29. Rennert P. D., Heinrich G. Nerve growth factor mRNA in brain: localization by in situ hybridization. Biochem Biophys Res Commun. 1986 Jul 31;138(2):813–818. doi: 10.1016/s0006-291x(86)80569-1. [DOI] [PubMed] [Google Scholar]
  30. Schwab M. E., Otten U., Agid Y., Thoenen H. Nerve growth factor (NGF) in the rat CNS: absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra. Brain Res. 1979 Jun 8;168(3):473–483. doi: 10.1016/0006-8993(79)90303-2. [DOI] [PubMed] [Google Scholar]
  31. Sheardown M. J., Nielsen E. O., Hansen A. J., Jacobsen P., Honoré T. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemia. Science. 1990 Feb 2;247(4942):571–574. doi: 10.1126/science.2154034. [DOI] [PubMed] [Google Scholar]
  32. Soppet D., Escandon E., Maragos J., Middlemas D. S., Reid S. W., Blair J., Burton L. E., Stanton B. R., Kaplan D. R., Hunter T. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell. 1991 May 31;65(5):895–903. doi: 10.1016/0092-8674(91)90396-g. [DOI] [PubMed] [Google Scholar]
  33. Spranger Matthias, Lindholm Dan, Bandtlow Christine, Heumann Rolf, Gnahn Hannes, Näher-Noé Martina, Thoenen Hans. Regulation of Nerve Growth Factor (NGF) Synthesis in the Rat Central Nervous System: Comparison between the Effects of Interleukin-1 and Various Growth Factors in Astrocyte Cultures and in vivo. Eur J Neurosci. 1990 Jan;2(1):69–76. doi: 10.1111/j.1460-9568.1990.tb00382.x. [DOI] [PubMed] [Google Scholar]
  34. Squinto S. P., Stitt T. N., Aldrich T. H., Davis S., Bianco S. M., Radziejewski C., Glass D. J., Masiakowski P., Furth M. E., Valenzuela D. M. trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell. 1991 May 31;65(5):885–893. doi: 10.1016/0092-8674(91)90395-F. [DOI] [PubMed] [Google Scholar]
  35. Wetmore C., Ernfors P., Persson H., Olson L. Localization of brain-derived neurotrophic factor mRNA to neurons in the brain by in situ hybridization. Exp Neurol. 1990 Aug;109(2):141–152. doi: 10.1016/0014-4886(90)90068-4. [DOI] [PubMed] [Google Scholar]
  36. Whittemore S. R., Friedman P. L., Larhammar D., Persson H., Gonzalez-Carvajal M., Holets V. R. Rat beta-nerve growth factor sequence and site of synthesis in the adult hippocampus. J Neurosci Res. 1988 Aug;20(4):403–410. doi: 10.1002/jnr.490200402. [DOI] [PubMed] [Google Scholar]
  37. Zafra F., Hengerer B., Leibrock J., Thoenen H., Lindholm D. Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J. 1990 Nov;9(11):3545–3550. doi: 10.1002/j.1460-2075.1990.tb07564.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES