Journal Article

Metabotropic glutamate receptors in the basal ganglia motor circuit

Conn, P. Jeffrey, Battaglia, Giuseppe, Nicoletti, Ferdinando, Marino, Michael J.

2005

Overview

Key Points An important achievement in the quest to bridge cellular and integrative neuroscience has been the development of an understanding of the basal ganglia motor circuit, how activity in this circuit affects motor behaviour and how changes in this circuit give rise to motor dysfunction in disorders such as Parkinson's disease (PD). This is a rare example of a field in which our understanding at a circuit level began with clinical studies in humans and studies in non-human primates. These findings are now driving studies at the cellular and molecular levels that, in turn, drive further studies at the behavioural and system levels. Metabotropic glutamate receptors (mGluRs) are richly distributed throughout the basal ganglia. We now have a growing appreciation of the distributions and functional roles of various mGluR subtypes in regulating activity throughout this circuit. In addition to providing new insights into mechanisms by which these receptors can regulate normal motor function, these studies indicate that mGluR ligands might be useful as novel therapeutic agents for the treatment of PD and other basal ganglia disorders. Activation of group I mGluRs (mGluR1 and mGluR5) has effects at various sites in the basal ganglia that could contribute to the overactivity that occurs at some synapses of this circuit in PD. This has led to the idea that antagonists of these receptors could have anti-parkinsonian effects. Recent behavioural studies with mGluR5-selective antagonists are consistent with this and show that blockade of this receptor reduces motor symptoms in parkinsonian animals. Activation of group II (mGluR2 and mGluR3) or group III (mGluR4) receptor subtypes reduces transmission at specific synapses that are overactive in patients with PD and parkinsonian animals. Again, behavioural studies reveal that activators of these receptors can have anti-parkinsonian effects. This is especially true for agonists or allosteric potentiators of mGluR4, which induce robust anti-parkinsonian effects in various rodent models. In addition to providing symptomatic relief of the motor symptoms of PD, recent studies suggest that the same mGluR ligands have potential for neuroprotective activity in both PD and Huntington's disease. Although the potential neuroprotective activity of these compounds has not been fully tested across many compounds and animal models, recent studies are promising and raise the possibility of combined symptomatic and neuroprotective activity in these compounds. In recent years there have been tremendous advances in our understanding of the circuitry of the basal ganglia and our ability to predict the behavioural effects of specific cellular changes in this circuit on voluntary movement. These advances, combined with a new understanding of the rich distribution and diverse physiological roles of metabotropic glutamate receptors in the basal ganglia, indicate that these receptors might have a key role in motor control and raise the exciting possibility that they might provide therapeutic targets for the treatment of Parkinson's disease and related disorders.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animal Genetics and Genomics / Animals / Basal Ganglia - physiology / Behavioral Sciences / Biological and medical sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Disease / Dopamine / Fundamental and applied biological sciences. Psychology / Humans / Ligands / Medical sciences / Motor control and motor pathways. Reflexes. Control centers of vegetative functions. Vestibular system and equilibration / Movement - physiology / Neural Pathways - physiology / Neurobiology / Neurology / Neurosciences / Parkinson's disease / R&D / Receptors, Metabotropic Glutamate - physiology / Research & development / review-article / Vertebrates: nervous system and sense organs