Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons

Medium spiny neurons were recorded from striatal slices obtained from mice lacking the group I metabotropic glutamate receptor (mGluR) subtype 1 or su btype 5. In wild-type animals, N-methyl-D-aspartate (NMDA)-induced membrane depolarization/inward currents were potentiated in the presence of both th e group I mGluR agonist 3,5-dihydroxyphenylglycine (3,5-DHPG) and the mGluR 5 selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG). Likewise. in mGluR1 knockout mice, both 3.5-DHPG and CHPG were able to potentiate NMD A responses. Conversely. in neurons recorded from mCluR5-deficient mice, th e enhancement of NMDA responses by both 3,5-DHPG and CHPG was absent. Pharm acological analysis performed from rat slices confirmed the data obtained w ith mice. In the presence of the competitive mGluR1 antagonist LY367385, th e NMDA responses were potentiated in the presence of CHPG, whereas the CHPG -induced enhancement was not observed in slices treated with the non-compet itive mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine. As in wild-typ e mice, in neither of the mGluR1- and mGluR5-deficient mice did (2S,1' R.2' R,3' R)-2-(2,3-dicarboxylcyclopropyl)-glycine (1 muM), nor L-serine-O-phos phate (30 muM) (agonists for group II and III mGIuRs, respectively) affect the NMDA-evoked responses. In striatal medium spiny neurons, NMDA responses are potentiated by endogen ous acetylcholine via MI-like muscarinic receptors. Since the enhancement o f NMDA responses by 3,5-DHPG and by M1-like muscarinmic agonists was shown to share common post-receptor mechanisms, we verified whether the muscarini c potentiation of NMDA responses was affected in these group I mGluR-defici ent mice. Both in mGluR1 and mGluR5 knockout animals, in the presence of ei ther muscarine or the M1-like muscarinic receptor agonist McN-A-343, the po sitive modulation of the NMDA-induced membrane depolarization persisted. These results confirm the permissive role of group I mGluRs on NMDA respons es in striatal neurons and reveal that this functional interplay occurs exc lusively through the mGluR5 subtype, The NMDA-mGluR5 interaction might play an important modulatory role in the final excitatory drive from corticostr iatal afferents and suggests that drugs acting at mGluR5 might prove useful for the treatment of movement disorders involving the striatum. (C) 2001 I BRO. Published by Elsevier Science Ltd. All rights reserved.