Skip to main content
Log in

Neurotrophic effects of NMDA receptor activation on developing cerebellar granule cells

  • Published:
Journal of Neurocytology

Summary

Glutamate acting on N-methyl-D-aspartate (NMDA) receptors controls a variety of aspects of neuronal plasticity in the adult and developing brain. This review summarizes its effects on developing cerebellar granule cells. The glutamatergic mossy fibre input to cerebellar granule cells exerts a neurotrophic effect on these cells during development. The investigation of potential neurotrophic agents can be carried out using enriched granule cell cultures. Considerable evidence now indicates that glutamate acting on N-methyl-D-aspartate receptors is an important neurotrophic factor that regulates granule cell development. In culture, neurite growth, differentiation and cell survival are all stimulated by N-methyl-D-aspartate receptor activation. The intracellular pathways involved following Ca2+ entry through the N-methyl-D-aspartate receptor channel are beginning to be elucidated. The cerebellar granule cell culture system may provide an ideal model to investigate the molecular mechanisms involved in long term N-methyl-D-aspartate receptor-mediated changes in neuronal function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Altman, J. (1982) Morphological development of the rat cerebellum and some of its mechanisms.Experimental Brain Research Supplement6, 8–49.

    Google Scholar 

  • Aruffo, C., Ferszt, R., Hildebrandt, A. G. &Cervos-Navarro, J. (1987) Low doses ofl-monosodium glutamate promote neuronal growth and differentiationin vitro.Developmental Neuroscience 9, 228–39.

    PubMed  Google Scholar 

  • Balazs, R., Hack, N. &Jorgensen, O. S. (1988a) Stimulation of the N-methyl-D-asparate receptor has a trophic effect on differentiating cerebellar granule cells.Neuroscience Letters 87, 80–6.

    PubMed  Google Scholar 

  • Balazs, R., Jorgensen, O. S. &Hack, N. (1988b) N-methyl-D-aspartate promotes the survival of cerebellar granule cells in culture.Neuroscience 27, 437–51.

    PubMed  Google Scholar 

  • Balazs, R., Hack, N. &Jorgensen, O. S. (1990a) Interactive effect involving different classes of excitatory amino acid receptors and the survival of cerebellar granule cells in culture.International Journal of Developmental Neuroscience 8, 347–59.

    PubMed  Google Scholar 

  • Balazs, R., Hack, N. &Jorgensen, O. S. (1990b) Selective stimulation of excitatory amino acid receptor subtypes and the survival of cerebellar granule cells in culture: effect of kainic acid.Neuroscience 37, 251–8.

    PubMed  Google Scholar 

  • Balazs, R., Hack, N., Resink, A., Aronica, E. &Van Der Valk, J. B. F. (1992a) Trophic effect of excitatory acids on differentiating granule cells: involvement of calcium and other second messengers.Molecular Neuropharmacology (in press).

  • Balazs, R., Resink, A., Hack, N., Van Der Valk, J. B. F., Kumar, K. K. &Michaelis, E. (1992b) NMDA treatment and K+-induced depolarization selectively promote the expression of an NMDA-preferring class of the ionotropic glutamate receptors in cerebellar granule neurons.Neuroscience Letters 137, 109–13.

    PubMed  Google Scholar 

  • Berciano, M. T. &Lafarga, M. (1988) Colony-forming extopic granule cells in the cerebellar primary fissure of normal adult rats: a morphological and morphometric study.Brain Research 439, 169–78.

    PubMed  Google Scholar 

  • Bigot, D., Matus, A. &Hunt, S. P. (1991) Reorganization of the cytoskeleton in rat neurons following stimulation with excitatory amino acids in vitro.European Journal of Neuroscience 3, 551–8.

    PubMed  Google Scholar 

  • Brenneman, D. E., Forsythe, I. D., Nicol, T. &Nelson, P. G. (1990) N-methyl-D-aspartate receptors influence neuronal survival in developing spinal cord cultures.Developmental Brain Reasearch 51, 63–8.

    Google Scholar 

  • Brewer, G. J. &Cotman, C. W. (1989) NMDA receptor regulation of neuronal morphology in cultured hippocampal neurons.Neuroscience Letters 99, 268–73.

    PubMed  Google Scholar 

  • Burgoyne, R. D., Pearce, I. A. &Cambray-Deakin, M. A. (1988) N-methyl-D-aspartate raises cytosouc calcium concentration in rat cerebellar granule cells in culture.Neuroscience Letters 91, 47–52.

    PubMed  Google Scholar 

  • Burgoyne, R. D. &Cambray-Deakin, M. A. (1988) The cellular neurobiology of neuronal development: the cerebellar granule cell.Developmental Brain Research 13, 77–101.

    Google Scholar 

  • Cambray-Deakin, M. A., Morgan, A. &Burgoyne, R. D. (1987) Sequential appearance of cytoskeletal components during early stages of neurite outgrowth from cerebellar granule cellsin vitro.Developmental Brain Research 37, 197–207.

    Google Scholar 

  • Cambray-Deakin, M. A., Adu, J. &Burgoyne, R. D. (1990a) Neuritogenesis in cerebellar granule cells in vitro: a role for protein kinase C.Developmental Brain Research 53, 40–6.

    PubMed  Google Scholar 

  • Cambray-Deakin, M. A., Foster, A. C. &Burgoyne, R. D. (1990b) The expression of excitatory amino acid binding sites during neuritogenesis in the developing rat cerebellum.Developmental Brain Research 54, 265–71.

    PubMed  Google Scholar 

  • Cambray-Deakin, M. A. &Burgoyne, R. D. (1990) Regulation of neurite outgrowth from cerebellar granule cells in culture: NMDA receptors and protein kinase C.Advances in Experimental Medicine and Biology 268, 245–53.

    PubMed  Google Scholar 

  • Cambray-Deakin, M. A. &Burgoyne, R. D. (1992) Intracellular Ca2+ and N-methyl-D-aspartate-stimulated neuritogenesis in rat cerebellar granule cell cultures.Developmental Brain Research 66, 25–32.

    PubMed  Google Scholar 

  • Cline, H. T., Debski, E. A. &Constantine-Paton, M. (1987) N-methyl-D-aspartate receptor antagonist desegregates eye-specific strips.Proceedings of the National Academy of Sciences (USA) 84, 4342–5.

    Google Scholar 

  • Collingridge, G. L. &Singer, W. (1991) Excitatory amino acid receptors and synaptic plasticity.Trends in Pharmacological Sciences 11, 290–6.

    Google Scholar 

  • Didier, M., Roux, P., Piechaczyk, M., Verrier, B., Bockaert, J. &Pin, J. -P. (1989) Cerebellar granule cell survival and maturation induced by K+ and NMDA correlate with c-fos proto-oncogene expression.Neuroscience Letters 107, 55–62.

    PubMed  Google Scholar 

  • Didier, M., Roux, P., Piechaczyk, M., Mangeat, P., Devilliers, G., Bockaert, J. &Pin, J. P. (1992) Longterm expression of the c-fos protein during thein vitro differentiation of cerebellar granule cells induced by potassium or NMDA.Molecular Brain Research 12, 249–58.

    PubMed  Google Scholar 

  • Garthwaite, G., Yamini, B. &Garthwaite, J. (1987) Selective loss of Purkinje and granule cell responsiveness to N-methyl-D-aspartate in rat cerebellum during development.Developmental Brain Research 36, 288–92.

    Google Scholar 

  • Garthwaite, J. &Brodbelt, A. R. (1989) Synaptic activation of N-methyl-D-asparate and non N-methyl-D-aspartate receptors in the mossy fibre pathway in adult and immature rat cerebellar slices.Neuroscience 29, 401–12.

    PubMed  Google Scholar 

  • Graham, M. E. &Burgoyne, R. D. (1991) N-methyl-D-aspartate stimulation of the survival of rat cerebellar granule cells in culture is not dependent upon increased c-fos expression and is not mimicked by protein kinase C activation.Neuroscience Letters 130, 267–70.

    PubMed  Google Scholar 

  • Graham, M. E. &Burgoyne, R. D. (1993) Phosphoproteins of cultured cerebellar granule cells and responses to the differentiation-promoting stimuli NMDA, high K+ and ionomycin,European Journal of Neuroscience 5, 575–583.

    PubMed  Google Scholar 

  • Gray, E. G. (1961) The granule cells, mossy fibres and Purkinje spine synapses of the cerebellum: light and electron microscope observations.Journal of Anatomy 95, 345–56.

    PubMed  Google Scholar 

  • Gu, Q., Bear, M. F. &Singer, W. (1989) Blockade of NMDA-receptors prevents ocularity changes in kitten visual cortex after reversed monocular deprivation.Developmental Brain Research 47, 281–8.

    PubMed  Google Scholar 

  • Hahm, J. O., Langdon, R. B. &Sur, M. (1991) Disruption of retinogeniculate afferent segregation by antagonists to NMDA receptors.Nature 351, 568–70.

    PubMed  Google Scholar 

  • Hamori, J. &Somogyi, J. (1983) Differentation of cerebellar mossy fibre synapses in the rat: a quantitative electron microscope study.Journal of Comparative Neurology 220, 365–77.

    PubMed  Google Scholar 

  • Hansen, G. H., Meier, E. &Schousboe, A. (1984) GABA influences the ultrastructure composition of cerebellar granule cells during development in culture.International Journal of Developmental Neuroscience 2, 247–57.

    Google Scholar 

  • Jones, P. G. &Bulloch, A. G. M. (1988)l-Glutamate promotes neurite outgrowth in adult Helisoma neurons.Neuroscience Research Communications 3, 93–9.

    Google Scholar 

  • Kalb, R. G. &Hockfield, S. (1990) Induction of a neuronal proteoglycan by the NMDA receptor in the developing spinal cord.Science 250, 294–6.

    PubMed  Google Scholar 

  • Kilic, G., Moran, O. &Cherubini, E. (1991) N-methyl-D-aspartate receptor-mediated spontaneous activity in cerebellar granule cells in culture.Neuroscience Letters 130, 263–6.

    PubMed  Google Scholar 

  • Kleinschmidt, J. A., Bear, M. F. &Singer, W. (1987) Blockade of NMDA receptors disrupts experience-dependent plasticity of the kitten striate cortex.Science 238, 355–8.

    PubMed  Google Scholar 

  • Lasher, R. S. &Zagon, I. S. (1972) The effect of potassium on the neuronal differentiation in culture of dissociated newborn rat cerebellum.Brain Research 41, 482–8.

    PubMed  Google Scholar 

  • Martin, D. P., Schmidt, R. E., Distefano, P. S., Lowry, O. H., Carter, J. G. &Johnson, E. M. (1988) Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation.Journal of Cell Biology 106, 829–14.

    PubMed  Google Scholar 

  • Mattson, M. P., Lee, R. E., Adams, M. E., Guthrie, P. B. &Kater, S. B. (1988) Interactions between entorhinal axons and target hippocampal neurons: a role for glutamate in the development of hippocampal circuitry.Neuron 1, 865–76.

    PubMed  Google Scholar 

  • Meier, E., Hansen, G. H. &Shousboe, A. (1985) The trophic effect of GABA on cerebellar granule cells in mediated by GABA-receptors.International Journal of Developmental Neuroscience 3, 401–7.

    Google Scholar 

  • Meier, E. &Jorgensen, O. S. (1986) γ-aminobutyric acid affects the developmental expression of neuron-associated proteins in cerebellar granule cell cultures.Journal of Neurochemistry 46, 1256–62.

    PubMed  Google Scholar 

  • Moran, J. &Patel, A. J. (1989) Stimulation of the N-methyl-D-aspartate receptor promotes the biochemical differentiation of cerebellar granule neurons and not astrocytes.Developmental Brain Research 486, 15–25.

    Google Scholar 

  • Pearce, B. R. &Dutton, G. R. (1981) K+-stimulated release of endogenous glutamate, GABA and other amino acids from neuron- and glia-enriched cultures of the rat cerebellum.FEBS Letters 135, 215–18.

    PubMed  Google Scholar 

  • Pearce, I. A., Cambray-Deakin, M. A. &Burgoyne, R. D. (1987) Glutamate acting on NMDA receptors stimulates neurite outgrowth from cerebellar granule cells.FEBS Letters 223, 143–7.

    PubMed  Google Scholar 

  • Pearson, H., Graham, M. E. &Burgoyne, R. D. (1992a) Effect of growth in depolarising conditions of the expression of N-methyl-D-aspartate responses in rat cerebellar granule cells in culture.Neuroscience Letters 142, 27–30.

    PubMed  Google Scholar 

  • Pearson, H., Graham, M. E. &Burgoyne, R. D. (1992b) Relationship between intracellular free calcium concentration and NMDA-induced cerebellar granule cell survivalin vitro.European Journal of Neuroscience 4, 1369–1375.

    PubMed  Google Scholar 

  • Rakic, P. &Sidman, R. L. (1977) Organization of the cerebellar cortex secondary to deficit of granule cells in weaver mutant mice.Journal of Comparative Neurology 152, 133–62.

    Google Scholar 

  • Rashid, N. A. &Cambray-Deakin, M. A. (1992) N-methyl-D-aspartate effects on the growth, morphology and cytoskeleton of individual neurons in vitro.Developmental Brain Research (in press).

  • Rodriguez, J., Jacques-Berg, W. &Patel, A. J. (1991) Differential regulation of cerebellar granule neurons by two types of quisqualate receptors.Neuroreport 2, 517–20.

    PubMed  Google Scholar 

  • Scholz, W. K. &Palfrey, H. C. (1991) Glutamate-stimulated protein phosphorylation in cultured hippo-campal pyramidal neurons.Journal of Neuroscience 11, 2442–52.

    Google Scholar 

  • Van Der Valk, J. B. F., Resink, A. &Balazs, R. (1991) Membrane depolarisation and the expression of glutamate receptors in cerebellar granule cells.European journal Pharmacology 201, 247–50.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burgoyne, R.D., Graham, M.E. & Cambray-Deakin, M. Neurotrophic effects of NMDA receptor activation on developing cerebellar granule cells. J Neurocytol 22, 689–695 (1993). https://doi.org/10.1007/BF01181314

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01181314

Keywords

Navigation