Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus

• Type of Material: Article
• Authors: Hazar Awad, Emory University; George W. Hubert, Emory University; Yoland Smith, Emory University; Allan Levey, Emory University; P. Jeffrey Conn, Emory University
• Language: English
• Date: 2000-11-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2000 Society for Neuroscience
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.20-21-07871.2000
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 20
• Issue: 21
• Start Page: 7871
• End Page: 7879
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health National Institute of Neurological Disorders and Stroke; the Tourette's Syndrome Foundatio; and the US Army Medical Research and Material Command.
• Keywords: STIMULATION; FUNCTIONAL-ANATOMY; metabotropic glutamate receptor; HIPPOCAMPUS; mGluR5; AGONIST; Neurosciences; Neurosciences & Neurology; burst firing; BASAL GANGLIA; Parkinson's disease; basal ganglia; STRIATAL NEURONS; Science & Technology; RAT-BRAIN; SYNAPTIC TRANSMISSION; subthalamic nucleus; NMDA receptor; IMMUNOHISTOCHEMICAL LOCALIZATION; mGluR1; Life Sciences & Biomedicine; GLOBUS-PALLIDUS
• Research Categories: Biology, Neuroscience; Health Sciences, Pharmacology

Abstract

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor function, as well as in pathological conditions such as Parkinson's disease (PD) and related disorders. Development of a complete understanding of the roles of the STN in motor control and the pathophysiological changes in STN that underlie PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces a direct excitation of STN neurons that is characterized by depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective potentiation of NMDA-evoked currents. Immunohistochemical studies at the light and electron microscopic levels indicate that both subtypes of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects is attributable to activation of mGluR5, not mGluR1, despite the presence of both subtypes in STN neurons. These results suggest that mGluR5 may play an important role in the net excitatory drive to the STN from glutamatergic afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatment of a variety of movement disorders that involve changes in STN activity.