Elsevier

Neuroscience

Volume 106, Issue 3, 27 September 2001, Pages 579-587
Neuroscience

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

https://doi.org/10.1016/S0306-4522(01)00297-4Get rights and content

Abstract

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 μM), nor L-serine-O-phosphate (30 μM) (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.

Section snippets

Preparation and maintenance of the slices

Medium spiny striatal neurons (n=121) were recorded from slices obtained from wild-type, mGluR1 or 5 knockout (−/−) mice (Conquet et al., 1994, Chiamulera et al., 2001). Another set of experiments was performed from male Wistar rats (Harlan, Italy). Preparation and maintenance of the slices have been previously described and are in accordance with the European Community Council Directive (86/609/EEC) (Calabresi et al., 1993, Calabresi et al., 1998, Pisani et al., 1997a, Pisani et al., 1997b).

Electrophysiological properties of the recorded cells

Conventional sharp microelectrode recordings were performed from electrophysiologically identified medium spiny neurons, both in the current- and voltage-clamp mode. The main characteristics of spiny neurons have been extensively described previously (Calabresi et al., 1990, Calabresi et al., 1992). The parameters in Table 1 were considered in order to compare wild-type and knockout mice. No significant difference in the intrinsic membrane properties (resting membrane potential, input

Discussion

In the present study we extended our previous observations on the facilitatory role of group I mGluRs on the responses to NMDA in medium spiny striatal neurons, providing evidence that this effect occurs through the activation of mGluR5. The lack of enhancement of NMDA responses in mGluR5 knockout mice by 3,5-DHPG and, conversely, the persistence of this effect in mice deficient for mGluR1 are in support of this hypothesis. It should be noticed that, as observed previously in a rat preparation (

Acknowledgements

We wish to thank Mr. M. Tolu for the excellent technical assistance provided. This work was supported by a M.U.R.S.T. grant (Cofinanziamento 1998 and 2000) to G.B., by a grant from Ministero della Sanità (Progetto Finalizzato ’98 and Progetto Finalizzato Alzheimer) to A.P.

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