Neuropharmacology 40 (2001) 839–846 www.elsevier.com/locate/neuropharm Selective involvement of mGlu1 receptors in corticostriatal LTD Paolo Gubellini a, b, c , Emilia Saulle a, b , Diego Centonze a, b , Paola Bonsi a, b , Antonio Pisani a, b , Giorgio Bernardi a, b , Franc ¸ois Conquet d , Paolo Calabresi a, b,* a Clinica Neurologica, Dipartimento di Neuroscienze, Universita ` “Tor Vergata”, Via di Tor Vergata 135, 00133 Rome, Italy b IRCCS Fondazione Santa Lucia, Rome, Italy c Istituto di Neuroscienze e Medicina Molecolare, CNR, Rome, Italy d Glaxo Wellcome Experimental Research, IBCM, Lausanne, Switzerland Received 14 December 2000; received in revised form 29 January 2001; accepted 31 January 2001 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.  2001 Elsevier Science Ltd. All rights reserved. Keywords: Synaptic plasticity; Electrophysiology; Glutamate; Transgenic mice; Group I metabotropic glutamate receptors; AIDA; LY 367385 1. Introduction Metabotropic glutamate receptors (mGluRs) are involved in various forms of synaptic plasticity in differ- ent brain areas (Nicoll et al., 1998; Anwyl, 1999; Bortol- otto 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 sub- type-selective antagonists has provided the possibility to identify multiple and differential roles mGluRs in synap- tic plasticity (for a review see Anwyl, 1999). Nevertheless, the role of mGluRs in synaptic plasticity * Corresponding author. Tel.: +39-06-7259-6010 fax: +39-06- 7259-6006. E-mail address: calabre@uniroma2.it (P. Calabresi). 0028-3908/01/$ - see front matter  2001 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(01)00021-1 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 con- cerning the exact involvement of mGluRs in the induc- tion of various forms of long-term potentiation (LTP) and long-term depression (LTD). In fact, while infor- mation 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 contri- bution 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 adapt- ive 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