Skip to main content
NCBI 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
. 1992 Jun 1;89(11):5197–5200. doi: 10.1073/pnas.89.11.5197

Reduction of posttraumatic transneuronal "early gene" activation and dendritic atrophy by the N-methyl-D-aspartate receptor antagonist MK-801.

R Nitsch 1, M Frotscher 1
PMCID: PMC49257  PMID: 1534412

Abstract

The removal of a major hippocampal afferent system, the glutamatergic fibers from the entorhinal cortex, results in transneuronal changes in postsynaptic inhibitory neurons using gamma-aminobutyric acid (GABA) as a neurotransmitter. This study shows that these transneuronal alterations are reduced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801. Thus, systemic injection of (+)-MK-801 prior to and after entorhinal lesion abolishes the retraction of distal dendrites from the termination zones of degenerating entorhinal fibers and reduces the swelling of their distal segments. Also, entorhinal lesion results in the appearance of c-fos protein-like immunoreactivity in hippocampal neurons and glial cells, which again is blocked by (+)-MK-801 administration. These data suggest that NMDA receptor-mediated neurotoxicity due to postlesional glutamate elevation results in early gene expression and in transneuronal dendritic changes. Similar processes may play a role in Alzheimer's disease, since there is a severe degeneration of the glutamatergic entorhino-hippocampal projection in this neurodegenerative disorder.

Full text

PDF
5197

Images in this article

5198Image
on p.5198
5198Image
on p.5198
5199Image
on p.5199

Selected References

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

  1. Auer R., Kalimo H., Olsson Y., Wieloch T. The dentate gyrus in hypoglycemia: pathology implicating excitotoxin-mediated neuronal necrosis. Acta Neuropathol. 1985;67(3-4):279–288. doi: 10.1007/BF00687813. [DOI] [PubMed] [Google Scholar]
  2. Benveniste H., Drejer J., Schousboe A., Diemer N. H. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem. 1984 Nov;43(5):1369–1374. doi: 10.1111/j.1471-4159.1984.tb05396.x. [DOI] [PubMed] [Google Scholar]
  3. Celio M. R., Baier W., Schärer L., de Viragh P. A., Gerday C. Monoclonal antibodies directed against the calcium binding protein parvalbumin. Cell Calcium. 1988 Apr;9(2):81–86. doi: 10.1016/0143-4160(88)90027-9. [DOI] [PubMed] [Google Scholar]
  4. Choi D. W. Ionic dependence of glutamate neurotoxicity. J Neurosci. 1987 Feb;7(2):369–379. doi: 10.1523/JNEUROSCI.07-02-00369.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cole A. J., Saffen D. W., Baraban J. M., Worley P. F. Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature. 1989 Aug 10;340(6233):474–476. doi: 10.1038/340474a0. [DOI] [PubMed] [Google Scholar]
  6. De Boni U., McLachlan D. R. Controlled induction of paired helical filaments of the Alzheimer type in cultured human neurons, by glutamate and aspartate. J Neurol Sci. 1985 May;68(2-3):105–118. doi: 10.1016/0022-510x(85)90093-0. [DOI] [PubMed] [Google Scholar]
  7. Foster A. C., Gill R., Woodruff G. N. Neuroprotective effects of MK-801 in vivo: selectivity and evidence for delayed degeneration mediated by NMDA receptor activation. J Neurosci. 1988 Dec;8(12):4745–4754. doi: 10.1523/JNEUROSCI.08-12-04745.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Garthwaite G., Garthwaite J. Differential dependence on Ca2+ of N-methyl-D-aspartate and quisqualate neurotoxicity in young rat hippocampal slices. Neurosci Lett. 1989 Feb 27;97(3):316–322. doi: 10.1016/0304-3940(89)90617-4. [DOI] [PubMed] [Google Scholar]
  9. Hof P. R., Cox K., Young W. G., Celio M. R., Rogers J., Morrison J. H. Parvalbumin-immunoreactive neurons in the neocortex are resistant to degeneration in Alzheimer's disease. J Neuropathol Exp Neurol. 1991 Jul;50(4):451–462. doi: 10.1097/00005072-199107000-00006. [DOI] [PubMed] [Google Scholar]
  10. Hyman B. T., Van Hoesen G. W., Damasio A. R., Barnes C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science. 1984 Sep 14;225(4667):1168–1170. doi: 10.1126/science.6474172. [DOI] [PubMed] [Google Scholar]
  11. Isokawa M., Levesque M. F. Increased NMDA responses and dendritic degeneration in human epileptic hippocampal neurons in slices. Neurosci Lett. 1991 Nov 11;132(2):212–216. doi: 10.1016/0304-3940(91)90304-c. [DOI] [PubMed] [Google Scholar]
  12. Kleinschmidt A., Bear M. F., Singer W. Blockade of "NMDA" receptors disrupts experience-dependent plasticity of kitten striate cortex. Science. 1987 Oct 16;238(4825):355–358. doi: 10.1126/science.2443978. [DOI] [PubMed] [Google Scholar]
  13. Matthews D. A., Cotman C., Lynch G. An electron microscopic study of lesion-induced synaptogenesis in the dentate gyrus of the adult rat. I. Magnitude and time course of degeneration. Brain Res. 1976 Oct 8;115(1):1–21. doi: 10.1016/0006-8993(76)90819-2. [DOI] [PubMed] [Google Scholar]
  14. Mattson M. P. Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons. Neuron. 1990 Jan;4(1):105–117. doi: 10.1016/0896-6273(90)90447-n. [DOI] [PubMed] [Google Scholar]
  15. May P. C., Lampert-Etchells M., Johnson S. A., Poirier J., Masters J. N., Finch C. E. Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron. 1990 Dec;5(6):831–839. doi: 10.1016/0896-6273(90)90342-d. [DOI] [PubMed] [Google Scholar]
  16. Morgan J. I., Curran T. Role of ion flux in the control of c-fos expression. Nature. 1986 Aug 7;322(6079):552–555. doi: 10.1038/322552a0. [DOI] [PubMed] [Google Scholar]
  17. Nitsch R., Frotscher M. Maintenance of peripheral dendrites of GABAergic neurons requires specific input. Brain Res. 1991 Jul 19;554(1-2):304–307. doi: 10.1016/0006-8993(91)90205-a. [DOI] [PubMed] [Google Scholar]
  18. Nitsch R., Soriano E., Frotscher M. The parvalbumin-containing nonpyramidal neurons in the rat hippocampus. Anat Embryol (Berl) 1990;181(5):413–425. doi: 10.1007/BF02433788. [DOI] [PubMed] [Google Scholar]
  19. Phillips L. L., Steward O. Increases in mRNA for cytoskeletal proteins in the denervated neuropil of the dentate gyrus: an in situ hybridization study using riboprobes for beta-actin and beta-tubulin. Brain Res Mol Brain Res. 1990 Aug;8(3):249–257. doi: 10.1016/0169-328x(90)90024-8. [DOI] [PubMed] [Google Scholar]
  20. Rothman S. M., Thurston J. H., Hauhart R. E. Delayed neurotoxicity of excitatory amino acids in vitro. Neuroscience. 1987 Aug;22(2):471–480. doi: 10.1016/0306-4522(87)90347-2. [DOI] [PubMed] [Google Scholar]
  21. Seawright A. A., Brown A. W., Nolan C. C., Cavanagh J. B. Selective degeneration of cerebellar cortical neurons caused by cycad neurotoxin, L-beta-methylaminoalanine (L-BMAA), in rats. Neuropathol Appl Neurobiol. 1990 Apr;16(2):153–169. doi: 10.1111/j.1365-2990.1990.tb00944.x. [DOI] [PubMed] [Google Scholar]
  22. Simon R. P., Griffiths T., Evans M. C., Swan J. H., Meldrum B. S. Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: an electron microscopy study in the rat. J Cereb Blood Flow Metab. 1984 Sep;4(3):350–361. doi: 10.1038/jcbfm.1984.52. [DOI] [PubMed] [Google Scholar]
  23. Sloviter R. S. "Epileptic" brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies. Brain Res Bull. 1983 May;10(5):675–697. doi: 10.1016/0361-9230(83)90037-0. [DOI] [PubMed] [Google Scholar]
  24. Sonnenberg J. L., Mitchelmore C., Macgregor-Leon P. F., Hempstead J., Morgan J. I., Curran T. Glutamate receptor agonists increase the expression of Fos, Fra, and AP-1 DNA binding activity in the mammalian brain. J Neurosci Res. 1989 Sep;24(1):72–80. doi: 10.1002/jnr.490240111. [DOI] [PubMed] [Google Scholar]
  25. Spencer P. S., Nunn P. B., Hugon J., Ludolph A. C., Ross S. M., Roy D. N., Robertson R. C. Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin. Science. 1987 Jul 31;237(4814):517–522. doi: 10.1126/science.3603037. [DOI] [PubMed] [Google Scholar]
  26. Uemura Y., Kowall N. W., Beal M. F. Global ischemia induces NMDA receptor-mediated c-fos expression in neurons resistant to injury in gerbil hippocampus. Brain Res. 1991 Mar 1;542(2):343–347. doi: 10.1016/0006-8993(91)91589-s. [DOI] [PubMed] [Google Scholar]
  27. Weiss J. H., Choi D. W. Beta-N-methylamino-L-alanine neurotoxicity: requirement for bicarbonate as a cofactor. Science. 1988 Aug 19;241(4868):973–975. doi: 10.1126/science.3136549. [DOI] [PubMed] [Google Scholar]
  28. White J. D., Gall C. M., McKelvy J. F. Enkephalin biosynthesis and enkephalin gene expression are increased in hippocampal mossy fibers following a unilateral lesion of the hilus. J Neurosci. 1987 Mar;7(3):753–759. doi: 10.1523/JNEUROSCI.07-03-00753.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Zipp F., Nitsch R., Soriano E., Frotscher M. Entorhinal fibers form synaptic contacts on parvalbumin-immunoreactive neurons in the rat fascia dentata. Brain Res. 1989 Aug 21;495(1):161–166. doi: 10.1016/0006-8993(89)91231-6. [DOI] [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