Group III Metabotropic Glutamate Receptor-Mediated Modulation of the Striatopallidal Synapse

Abstract

The globus pallidus (GP) is a key GABAergic nucleus in the basal ganglia (BG). The predominant input to the GP is an inhibitory striatal projection that forms the first synapse in the indirect pathway. The GP GABAergic neurons project to the subthalamic nucleus, providing an inhibitory control of these glutamatergic cells. Given its place within the BG circuit, it is not surprising that alterations in GP firing pattern are postulated to play a role in both normal and pathological motor behavior. Because the inhibitory striatal input to the GP may play an important role in shaping these firing patterns, we set out to determine the role that the group III metabotropic glutamate receptors (GluRs) play in modulating transmission at the striatopallidal synapse. In rat midbrain slices, electrical stimulation of the striatum evoked GABA(A)-mediated IPSCs recorded in all three types of GP neurons. The group III mGluR-selective agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) inhibited these IPSCs through a presynaptic mechanism of action. L-AP4 exhibited high potency and a pharmacological profile consistent with mediation by mGluR4. Furthermore, the effect of L-AP4 on striatopallidal transmission was absent in mGluR4 knock-out mice, providing convincing evidence that mGluR4 mediates this effect. The finding that mGluR4 may selectively modulate striatopallidal transmission raises the interesting possibility that activation of mGluR4 could decrease the excessive inhibition of the GP that has been postulated to occur in Parkinson's disease. Consistent with this, we find that intracerebroventricular injections of L-AP4 produce therapeutic benefit in both acute and chronic rodent models of Parkinson's disease.

Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Reduces Nigrostriatal Degeneration in Mice Treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine

“…We decided to examine the role of mGlu4 receptors in MPTP toxicity because these receptors are one the most promising targets for symptomatic drugs in experimental parkinsonism. Activation of mGlu4 receptors suppresses GABA release from the striatopallidal terminals of the indirect pathway, thus relieving motor symptoms of parkinsonism Matsui and Kita, 2003;Valenti et al, 2003). mGlu4 receptor agonists/enhancers meet the requirement to be considered as "disease-dependent drugs" because they appear to act specifically on a pathway that is overactive in Parkinson's disease .…”

“…It is likely that the drug reduces the excitatory drive to the pars compacta of substantia nigra, thus limiting the excitotoxic component of MPTP toxicity (Turski et al, 1991;Srivastava et al, 1993;Lange and Riederer, 1994;Sonsalla et al, 1998). This may originate from (1) a reduced release of GABA in the external globus pallidus leading to inhibition of subthalamic glutamatergic neurons projecting to the pars compacta of substantia nigra Matsui and Kita, 2003;Valenti et al, 2003), or (2) a reduced glutamate release in the pars compacta of substantia nigra mediated by presynaptic mGlu4 receptors (Valenti et al, 2005). Infusion of PHCCC into the external globus pallidus protected the ipsilateral nigrostriatal pathway against MPTP toxicity to an extent similar to that found after systemic injection of the drug.…”

“…This leads to a disinhibition of GABAergic neurons projecting from the external globus pallidus to the subthalamic nucleus, with an ensuing inhibition of glutamatergic neurons of the subthalamic nucleus, which project to the internal globus pallidus and the pars reticulata of the substantia nigra. The following disinhibition of thalamocortical neurons results into an improvement of parkinsonian symptoms Valenti et al, 2003). Because neurons of the subthalamic nucleus also project to the pars compacta of the substantia nigra, one can predict that activation of mGlu4 receptors reduces the excitotoxic component of nigrostriatal degeneration in experimental models of parkinsonism.…”

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…Its strong expression at striatal GABAergic synapses in the GP and cortical glutamatergic synapses in the striatum, combined with electrophysiological in vitro data showing that its activation significantly reduces synaptic transmission at these key synapses of the basal ganglia circuitry Conn et al, 2005;Marino and Conn, 2006;Beurrier et al, 2009), has provided the rationale to examine the antiparkinsonian effects of mGluR4 agonists in rodent models of PD. Because of the lack of group III mGluRrelated compounds that could cross the blood-brain barrier, the original evidence that mGluR4 activation would alleviate PD symptoms came from studies using intracerebroventricular or intrapallidal administration of either the broad-spectrum group III mGluR agonist L-AP4 (L-2-amino-4-phosphono-butanoate) or the mGluR4 allosteric potentiator PHCCC (N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide) Valenti et al, 2003;Marino and Conn, 2006;Lopez et al, 2007Lopez et al, , 2008Johnson et al, 2009;Nicoletti et al, 2011).…”

Activation of Group III Metabotropic Glutamate Receptors Attenuates Rotenone Toxicity on Dopaminergic Neurons through a Microtubule-Dependent Mechanism

“…Because the rest of basal ganglia nuclei are largely intact, rebalancing the activities of the basal ganglia network by selective activation of certain metabotropic glutamate receptors appears to significantly alleviate PD-like symptoms in animal models (Conn et al, 2005). For example, intracerebroventricular injection of L-AP-4 markedly reduces locomotor deficiencies in various animal models of PD (Valenti et al, 2003;Macinnes et al, 2004). The neuroprotective effect of L-AP-4 on DA neurons (this study) may work synergistically with its ability to modulate synaptic transmission in non-DA neurons in basal ganglia (Conn et al, 2005), especially at the early stage of PD before the heavy loss of nigral DA neurons.…”