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

Journal of Neurochemistry - Tập 109 Số 4 - Trang 1096-1105 - 2009
Dario Cuomo1,2,3, Giuseppina Martella1,3, E. Barabino2,3, Paola Platania1, Daniela De Vita1, Graziella Madeo1, Chelliah Selvam4, Cyril Goudet5, Nadia Oueslati5, Jean‐Philippe Pin5, Francine Acher4, Antonio Pisani1,6, Corinne Beurrier2, Christophe Melon2, Lydia Kerkerian‐Le Goff2, Paolo Gubellini2
1Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma 'Tor Vergata', Rome, Italy
2Institut de Biologie du Développement de Marseille-Luminy, UMR6216 (CNRS, Université de la Méditerranée), Marseille, France
3These authors have contributed equally to the work.
4Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601 (CNRS, Université Paris Descartes), Paris, France
5Institut de Génomique Fonctionnelle, Département de Pharmacologie Moléculaire, UMR5203 (CNRS, INSERM U661, Université Montpellier I & II), Montpellier, France
6Fondazione Santa Lucia, IRCCS, Rome, Italy

Tóm tắt

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.

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Journal of Neurochemistry

Tập 109 Số 4

1096-1105

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