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 subtype 5. In wild-type animals, N-methyl-D-aspartate (NMDA)-induced membrane depolarization/inward currents were potentiated in the presence of both the group I mGluR agonist 3,5-dihydroxyphenylglycine (3,5-DHPG) and the mGluR5 selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG). Likewise, in mGluR1 knockout mice, both 3,5-DHPG and CHPG were able to potentiate NMDA responses. Conversely, in neurons recorded from mGluR5-deficient mice, the enhancement of NMDA responses by both 3,5-DHPG and CHPG was absent. Pharmacological analysis performed from rat slices confirmed the data obtained with mice. In the presence of the competitive mGluR1 antagonist LY367385, the NMDA responses were potentiated in the presence of CHPG, whereas the CHPG-induced enhancement was not observed in slices treated with the non-competitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine. As in wild-type mice, in neither of the mGluR1- and mGluR5-deficient mice did (2S,1'R,2'R,3'R)-2-(2,3-dicarboxylcyclopropyl)-glycine (1 microM), nor L-serine-O-phosphate (30 microM) (agonists for group II and III mGluRs, respectively) affect the NMDA-evoked responses. In striatal medium spiny neurons, NMDA responses are potentiated by endogenous acetylcholine via M1-like muscarinic receptors. Since the enhancement of NMDA responses by 3,5-DHPG and by M1-like muscarinic agonists was shown to share common post-receptor mechanisms, we verified whether the muscarinic potentiation of NMDA responses was affected in these group I mGluR-deficient mice. Both in mGluR1 and mGluR5 knockout animals, in the presence of either muscarine or the M1-like muscarinic receptor agonist McN-A-343, the positive modulation of the NMDA-induced membrane depolarization persisted.These results confirm the permissive role of group I mGluRs on NMDA responses in striatal neurons and reveal that this functional interplay occurs exclusively through the mGluR5 subtype. The NMDA-mGluR5 interaction might play an important modulatory role in the final excitatory drive from corticostriatal afferents and suggests that drugs acting at mGluR5 might prove useful for the treatment of movement disorders involving the striatum.
Pisani
A
A
Clinica Neurologica, Dipartmento di Neuroscienze, Università di Roma Tor Vergata, Rome, Italy. pisani@uniroma2.it
Gubellini
P
P
Bonsi
P
P
Conquet
F
F
Picconi
B
B
Centonze
D
D
Bernardi
G
G
Calabresi
P
P
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001565:Benzoates; D003521:Cyclopropanes / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009116:Muscarine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010648:Phenylacetates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
C107349:2-chloro-5-hydroxyphenylglycine; D000927:Anticonvulsants; D001565:Benzoates; D003521:Cyclopropanes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D018721:Muscarinic Agonists; D010648:Phenylacetates; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D012118:Resorcinols; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D018698:Glutamic Acid; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; C079215:3,5-dihydroxyphenylglycine; D016202:N-Methylaspartate; D009116:Muscarine; C121465:6-methyl-2-(phenylethynyl)pyridine; D005998:Glycine