Selective activation of mGlu4 metabotropic glutamate receptors is protective against excitotoxic neuronal death

V. Bruno, G. Battaglia, I. Ksiazek, H. Van Der Putten, M. V. Catania, R. Giuffrida, S. Lukic, T. Leonhardt, W. Inderbitzin, F. Gasparini, R. Kuhn, D. R. Hampson, F. Nicoletti, P. J. Flor

Research output: Contribution to journalArticle

Abstract

Activation of group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, and mGluR8) has been established to be neuroprotective in vitro and in vivo. To disclose the identity of the receptor subtype(s) that exert(s) the protective effect, we have used group III agonists in combination with mGluR4 subtype-deficient mice (-/-). In cortical cultures prepared from wild-type (+/+) mice and exposed to a toxic pulse of NMDA, the selective group III agonist (+)-4-phosphonophenylglycine [(+)-PPG] reversed excitotoxicity with an EC(50) value of 4.9 μM, whereas its enantiomer (-)-PPG was inactive. This correlated closely with the potency of (+)-PPG in activating recombinant mGluR4a. In cortical neurons from -/- mice, (+)-PPG showed no protection against the NMDA insult up to 300 μM, whereas group I/II mGluR ligands still retained their protective activity. Classical group III agonists (L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate) were also substantially neuroprotective against NMDA toxicity in +/+ and heterozygous (+/-) cultures but were inactive in -/- cultures. Interestingly, -/- cultures were more vulnerable to low concentrations of NMDA and showed higher extracellular glutamate levels compared with +/+ cultures. We have also examined neurodegeneration induced by intrastriatal infusion of NMDA in wild-type or mGluR4-deficient mice. Low doses of (R,S)-PPG (10 nmol/0.5 μl) substantially reduced NMDA toxicity in +/+ mice but were ineffective in -/- mice. Higher doses of (R,S)-PPG were neuroprotective in both strains of animals. Finally, microdialysis studies showed that intrastriatal infusion of NMDA increased extracellular glutamate levels to a greater extent in -/- than in +/+ mice, supporting the hypothesis that the mGluR4 subtype is necessary for the maintenance of the homeostasis of extracellular glutamate levels.

Original languageEnglish
Pages (from-to)6413-6420
Number of pages8
JournalJournal of Neuroscience
Volume20
Issue number17
Publication statusPublished - Sep 1 2000

Keywords

  • Cortical cultures
  • Excitotoxicity
  • Gene targeting
  • Knock-out mice
  • Metabotropic glutamate receptors
  • Neurodegeneration

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Bruno, V., Battaglia, G., Ksiazek, I., Van Der Putten, H., Catania, M. V., Giuffrida, R., Lukic, S., Leonhardt, T., Inderbitzin, W., Gasparini, F., Kuhn, R., Hampson, D. R., Nicoletti, F., & Flor, P. J. (2000). Selective activation of mGlu4 metabotropic glutamate receptors is protective against excitotoxic neuronal death. Journal of Neuroscience, 20(17), 6413-6420.