Corticostriatal LTP requires combined mGluR1 and mGluR5 activation

Abstract

Metabotropic glutamate receptors (mGluRs) have been demonstrated to play a role in synaptic plasticity. It has been recently shown that mGluR1 is involved in corticostriatal long-term depression, by means of pharmacological approach and by using mGluR1-knockout mice. Here, we report that both mGluR1 and mGluR5 are involved in corticostriatal long-term potentiation (LTP). In particular, the mGluR1 antagonist LY 367385, as well as the mGluR5 antagonist MPEP, reduce LTP amplitude. Moreover, blockade of both mGluR1 and mGluR5 by LY 367385 and MPEP co-administration fully suppresses LTP. Accordingly, group II and group III mGluRs antagonists fail to affect LTP induction. Interestingly, LTP amplitude is also significantly reduced in both mGluR1- and mGluR5-knockout mice.

The differential function of mGluR1 and mGluR5 in corticostriatal synaptic plasticity may play a role in the modulation of the motor activity mediated by the basal ganglia, thus providing a substrate for the pharmacological treatment of motor disorders involving the striatum.

Introduction

The involvement of metabotropic glutamate receptors (mGluRs) in synaptic plasticity has been recently demonstrated in different brain areas (Lu et al., 1997, Nicoll et al., 1998, Anwyl, 1999, Bortolotto et al., 1999, Dos Santos Villar and Walsh, 1999, Otani et al., 1999, Gubellini et al., 2001, Ichise et al., 2000, Sung et al., 2001). In particular, it has been shown in the striatum that group I mGluRs, i.e. mGluR1 and mGluR5, are involved in the induction of long-term depression (LTD). Nevertheless, the role of each of these receptors in the formation of corticostriatal LTD is still controversial, and the use of more selective ligands and gene-knockout mice did not completely clarify this issue (Dos Santos Villar and Walsh, 1999, Lovinger et al., 1999, Gubellini et al., 2001, Sung et al., 2001). Moreover, in this brain area it has not been characterized whether group I mGluRs contribute to the formation of long-term potentiation (LTP).

Also in other brain areas, the role of mGluRs in synaptic plasticity continues to be an open field for research. In the cerebellum, a critical role of mGluR1 for LTD has been demonstrated using gene KO (Conquet et al., 1994, Ichise et al., 2000, Neale et al., 2001), while LTP needs further studies. In the hippocampus, two forms of LTD have been demonstrated; one dependent on NMDA receptor activation, and the other dependent on mGluRs activation (Oliet et al., 1997, Otani and Connor, 1998). The latter form of LTD requires, in particular, the stimulation of group I mGluRs, which is per se sufficient to induce LTD in immature rat slices treated with the group I and II mGluR agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (Overstreet et al., 1997). Early reports on hippocampal LTP have shown that this form of synaptic plasticity is enhanced by (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), a group I and II mGluR agonist (McGuinness et al., 1991), while both NMDA receptor-dependent and independent LTP are blocked by the mGluR antagonist R,S-α-methyl-4-carboxyphenylglycine ((R,S)-MCPG) (Bashir et al., 1993). The interaction between NMDA receptor and mGluRs in hippocampal LTP has been further shown by Bortolotto et al. (1994).

More recently, however, the use of genetic approaches and the application of selective pharmacological compounds have provided conflicting results concerning the contribution of various subtypes of mGluRs in LTP and LTD (Bordi et al., 1997, Lu et al., 1997, Manahan-Vaughan, 1997, Wilsch et al., 1998, Balschun et al., 1999, Watabe et al., 2002).

However, the genetic disruption of a mGluR may cause adaptive changes that can either compensate the function of a certain gene or amplify the deficits resulting from the lack of a specific receptor. Moreover, some of the available pharmacological tools might lack specificity, thus they might be unable to distinguish between the various mGluR subtypes.

Thus, we have decided to apply a combined pharmacological and genetic approach to investigate the role of both mGluR1 and mGluR5 in corticostriatal LTP, which represent a well characterized form of synaptic plasticity in the brain (Calabresi et al., 1992b, Calabresi et al., 1996, Calabresi et al., 1999). Corticostriatal synaptic plasticity and striatum-dependent motor activity is regulated by drugs acting on mGluRs (Calabresi et al., 1992a, Sacaan et al., 1992, Lovinger and McCool, 1995, Schoepp et al., 1999, Gubellini et al., 2001, Sung et al., 2001). Moreover, mGluRs have been implicated in several experimental models of Parkinson’s disease (PD) (Konieczny et al., 1998, Bradley et al., 2000, Dawson et al., 2000), Huntington’s disease (HD) (Orlando et al., 1995, Beal et al., 1986, Cha et al., 1996, Pisani et al., 2001b), and excitoxicity (Bruno et al., 1995, Buisson and Choi, 1995, Cha et al., 1996). Thus, understanding the role of mGluRs in striatal synaptic plasticity might be important in order to define their potential role in these basal ganglia disorders.