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

Authors

  • Dario Cuomo,

    1. Institut de Biologie du Développement de Marseille-Luminy, UMR6216 (CNRS, Université de la Méditerranée), Marseille, France
    2. Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, Rome, Italy
    Search for more papers by this author
    • 1

      These authors have contributed equally to the work.

  • Giuseppina Martella,

    1. Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, Rome, Italy
    Search for more papers by this author
    • 1

      These authors have contributed equally to the work.

  • Emanuela Barabino,

    1. Institut de Biologie du Développement de Marseille-Luminy, UMR6216 (CNRS, Université de la Méditerranée), Marseille, France
    Search for more papers by this author
    • 1

      These authors have contributed equally to the work.

  • Paola Platania,

    1. Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, Rome, Italy
    Search for more papers by this author
  • Daniela Vita,

    1. Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, Rome, Italy
    Search for more papers by this author
  • Graziella Madeo,

    1. Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, Rome, Italy
    Search for more papers by this author
  • Chelliah Selvam,

    1. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601 (CNRS, Université Paris Descartes), Paris, France
    Search for more papers by this author
  • Cyril Goudet,

    1. Institut de Génomique Fonctionnelle, Département de Pharmacologie Moléculaire, UMR5203 (CNRS, INSERM U661, Université Montpellier I & II), Montpellier, France
    Search for more papers by this author
  • Nadia Oueslati,

    1. Institut de Génomique Fonctionnelle, Département de Pharmacologie Moléculaire, UMR5203 (CNRS, INSERM U661, Université Montpellier I & II), Montpellier, France
    Search for more papers by this author
  • Jean-Philippe Pin,

    1. Institut de Génomique Fonctionnelle, Département de Pharmacologie Moléculaire, UMR5203 (CNRS, INSERM U661, Université Montpellier I & II), Montpellier, France
    Search for more papers by this author
  • Francine Acher,

    1. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601 (CNRS, Université Paris Descartes), Paris, France
    Search for more papers by this author
  • Antonio Pisani,

    1. Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, Rome, Italy
    2. Fondazione ‘Santa Lucia’ IRCCS, Rome, Italy
    Search for more papers by this author
  • Corinne Beurrier,

    1. Institut de Biologie du Développement de Marseille-Luminy, UMR6216 (CNRS, Université de la Méditerranée), Marseille, France
    Search for more papers by this author
  • Christophe Melon,

    1. Institut de Biologie du Développement de Marseille-Luminy, UMR6216 (CNRS, Université de la Méditerranée), Marseille, France
    Search for more papers by this author
  • Lydia Kerkerian-Le Goff,

    1. Institut de Biologie du Développement de Marseille-Luminy, UMR6216 (CNRS, Université de la Méditerranée), Marseille, France
    Search for more papers by this author
  • Paolo Gubellini

    1. Institut de Biologie du Développement de Marseille-Luminy, UMR6216 (CNRS, Université de la Méditerranée), Marseille, France
    Search for more papers by this author

Address correspondence and reprint requests to Dr Paolo Gubellini, Équipe IC2N-IBDML UMR6216, Case 907 Parc Scientifique de Luminy, 13288 Marseille cedex 9, France.
E-mail: paolo.gubellini@ibdml.univ-mrs.fr

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.

Ancillary