Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson's disease treatment.
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)-alpha-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.
Cuomo
Dario
D
Institut de Biologie du Développement de Marseille-Luminy, UMR6216 CNRS, Université de la Méditerranée, Marseille, France.
Martella
Giuseppina
G
Barabino
Emanuela
E
Platania
Paola
P
Vita
Daniela
D
Madeo
Graziella
G
Selvam
Chelliah
C
Goudet
Cyril
C
Oueslati
Nadia
N
Pin
Jean-Philippe
JP
Acher
Francine
F
Pisani
Antonio
A
Beurrier
Corinne
C
Melon
Christophe
C
Kerkerian-Le Goff
Lydia
L
Gubellini
Paolo
P
D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D009068:Movement / Q000187:drug effects; D017072:Neostriatum / Q000502:physiology*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D013565:Sympatholytics; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000613:Aminobutyrates; D000978:Antiparkinson Agents; D018690:Excitatory Amino Acid Agonists; D018755:GABA Agonists; D018094:Receptors, Metabotropic Glutamate; D013565:Sympatholytics; D018698:Glutamic Acid; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; C012729:2-amino-4-phosphonobutyric acid; C108823:metabotropic glutamate receptor 4