Selective involvement of mGlu1 receptors in corticostriatal LTD

Abstract

Although metabotropic glutamate receptors (mGluRs) have been proposed to play a role in corticostriatal long-term depression (LTD), the specific receptor subtype required for this form of synaptic plasticity has not been characterized yet. Thus, we utilized a corticostriatal brain slice preparation and intracellular recordings from striatal spiny neurons to address this issue. We observed that both AIDA (100 μM) and LY 367385 (30 μM), two blockers of mGluR1s, were able to fully prevent the induction of this form of synaptic plasticity, whereas MPEP (30 μM), a selective antagonist of the mGluR5 subtype, did not significantly affect the amplitude and time-course of corticostriatal LTD. Both AIDA and LY 367385 were ineffective on LTD when applied after its induction. The critical role of mGluR1s in the formation of corticostriatal LTD was confirmed in experiments performed on mice lacking mGluR1s. In these mice, in fact, a significant reduction of the LTD amplitude was observed in comparison to the normal LTD measured in their wild-type counterparts. We found that neither acute pharmacological blockade of mGluR1s nor the genetic disruption of these receptors affected the presynaptic modulation of corticostriatal excitatory postsynapic potentials (EPSPs) exerted by DCG-IV and L-SOP, selective agonists of group II and III mGluRs, respectively.

Our data show that the induction of corticostriatal LTD requires the activation of mGluR1 but not mGluR5. mGluR1-mediated control of this form of synaptic plasticity may play a role in the modulatory effect exerted by mGluRs in the basal ganglia-related motor activity.

Introduction

Metabotropic glutamate receptors (mGluRs) are involved in various forms of synaptic plasticity in different brain areas (Nicoll et al., 1998, Anwyl, 1999, Bortolotto et al., 1999, Dos Santos Villar and Walsh, 1999, Otani et al., 1999, Ichise et al., 2000). The use of broad spectrum antagonists of mGluRs together with new subtype-selective antagonists has provided the possibility to identify multiple and differential roles mGluRs in synaptic plasticity (for a review see Anwyl, 1999).

Nevertheless, the role of mGluRs in synaptic plasticity continues to be a source of dispute. Even the use of more selective ligands and of selective gene knockouts (KO) has generated both progresses and controversies concerning the exact involvement of mGluRs in the induction of various forms of long-term potentiation (LTP) and long-term depression (LTD). In fact, while information resulting from gene KO demonstrated a critical role of mGluR1 in cerebellar LTD (Conquet et al., 1994, Ichise et al., 2000), 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 hippocampal LTP and LTD (Bordi et al., 1997, Lu et al., 1997). It is possible, in fact, that the genetic disruption causes adaptive changes that may either compensate the function of a certain gene or amplify the deficits resulting from the lack of a specific receptor. Conversely, some of the available pharmacological antagonists might lack specificity and for this reason they may be unable to distinguish between various mGluR subtypes. For this reason, the electrophysiological analysis on the role of mGluR in a certain form of synaptic plasticity should include both data from KO animals as well as information resulting from the acute pharmacological antagonism of the receptors.

Thus, we have decided to apply this combined approach to investigate the role of mGluRs in corticostriatal LTD, which represents a rather well-characterized form of synaptic plasticity in the brain (Calabresi et al., 1992, Calabresi et al., 1993, Calabresi et al., 1999, Lovinger et al., 1993, Walsh, 1993, Choi and Lovinger, 1997, Dos Santos Villar and Walsh, 1999). Three additional reasons have also motivated this study. First, previous studies have shown that broad spectrum antagonists of mGluRs block this form of synaptic plasticity (Calabresi et al., 1992, Lovinger et al., 1999), but the subtype involved in this effect has not been characterized. Second, drugs acting at mGluRs influence the striatum-dependent motor activity (Sacaan et al., 1992, Schoepp et al., 1992), suggesting that corticostriatal LTD may be important for the mGluR-mediated control of movement. Third, the modulation of mGluRs is able to reverse the motor abnormalities observed in experimental models of Parkinson's disease (Konieczny et al., 1998, Bradley et al., 2000, Dawson et al., 2000). Interestingly, experimental dopamine depletion causes also the loss of corticostriatal LTD (Calabresi et al., 1992, Calabresi et al., 2000a), suggesting a critical link between mGluRs and corticostriatal synaptic plasticity in Parkinson's disease.