Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: Implications for Parkinson's disease treatment

Dario Cuomo, Giuseppina Martella, Emanuela Barabino, Paola Platania, Daniela Vita, Graziella Madeo, Chelliah Selvam, Cyril Goudet, Nadia Oueslati, Jean Philippe Pin, Francine Acher, Antonio Pisani, Corinne Beurrier, Christophe Melon, Lydia Kerkerian-Le Goff, Paolo Gubellini

Research output: Contribution to journalArticle

Abstract

Alterations of striatal synaptic transmission have been associated with several motor disorders involving the basal ganglia, such as Parkinson's disease. For this reason, we investigated the role of group-III metabotropic glutamate (mGlu) receptors in regulating synaptic transmission in the striatum by electrophysiological recordings and by using our novel orthosteric agonist (3S)-3-[(3-amino-3-carboxypropyl(hydroxy)phosphinyl)-hydroxymethyl] -5-nitrothiophene (LSP1-3081) and l-2-amino-4-phosphonobutanoate (L-AP4). Here, we show that both drugs dose-dependently reduced glutamate- and GABA-mediated post-synaptic potentials, and increased the paired-pulse ratio. Moreover, they decreased the frequency, but not the amplitude, of glutamate and GABA spontaneous and miniature post-synaptic currents. Their inhibitory effect was abolished by (RS)-α-cyclopropyl-4-phosphonophenylglycine and was lost in slices from mGlu4 knock-out mice. Furthermore, (S)-3,4-dicarboxyphenylglycine did not affect glutamate and GABA transmission. Finally, intrastriatal LSP1-3081 or L-AP4 injection improved akinesia measured by the cylinder test. These results demonstrate that mGlu4 receptor selectively modulates striatal glutamate and GABA synaptic transmission, suggesting that it could represent an interesting target for selective pharmacological intervention in movement disorders involving basal ganglia circuitry.

Original languageEnglish
Pages (from-to)1096-1105
Number of pages10
JournalJournal of Neurochemistry
Volume109
Issue number4
DOIs
Publication statusPublished - May 2009

Keywords

  • γ-aminobutyric acid
  • Akinesia
  • Basal ganglia
  • Electrophysiology
  • Glutamate
  • Metabotropic glutamate receptor

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Cuomo, D., Martella, G., Barabino, E., Platania, P., Vita, D., Madeo, G., Selvam, C., Goudet, C., Oueslati, N., Pin, J. P., Acher, F., Pisani, A., Beurrier, C., Melon, C., Kerkerian-Le Goff, L., & Gubellini, P. (2009). Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: Implications for Parkinson's disease treatment. Journal of Neurochemistry, 109(4), 1096-1105. https://doi.org/10.1111/j.1471-4159.2009.06036.x