TY - JOUR
T1 - Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum
T2 - Implications for Parkinson's disease treatment
AU - Cuomo, Dario
AU - Martella, Giuseppina
AU - Barabino, Emanuela
AU - Platania, Paola
AU - Vita, Daniela
AU - Madeo, Graziella
AU - Selvam, Chelliah
AU - Goudet, Cyril
AU - Oueslati, Nadia
AU - Pin, Jean Philippe
AU - Acher, Francine
AU - Pisani, Antonio
AU - Beurrier, Corinne
AU - Melon, Christophe
AU - Kerkerian-Le Goff, Lydia
AU - Gubellini, Paolo
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
KW - γ-aminobutyric acid
KW - Akinesia
KW - Basal ganglia
KW - Electrophysiology
KW - Glutamate
KW - Metabotropic glutamate receptor
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UR - http://www.scopus.com/inward/citedby.url?scp=65649107339&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2009.06036.x
DO - 10.1111/j.1471-4159.2009.06036.x
M3 - Article
C2 - 19519781
AN - SCOPUS:65649107339
VL - 109
SP - 1096
EP - 1105
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 4
ER -