title: NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus.
abstract: The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)-P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease.
authors.affiliation: Department of Pharmacology and.
authors.forename: Sharon A
authors.identifier: http://orcid.org/0000-0003-0615-6244
authors.initials: SA
authors.lastname: Swanger
authors.affiliation: Department of Pharmacology and.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Vance
authors.affiliation: Yerkes National Primate Research Center and Morris K. Udall Center of Excellence for Parkinson's Disease Research, Emory University, Atlanta, Georgia 30329, and.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pare
authors.affiliation: H. Lundbeck A/S, Division of Neurodegeneration and Biologics, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Florence
authors.initials: F
authors.lastname: Sotty
authors.affiliation: H. Lundbeck A/S, Division of Neurodegeneration and Biologics, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Karina
authors.initials: K
authors.lastname: Fog
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, Yerkes National Primate Research Center and Morris K. Udall Center of Excellence for Parkinson's Disease Research, Emory University, Atlanta, Georgia 30329, and.
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.affiliation: Department of Pharmacology and strayne@emory.edu.
authors.forename: Stephen F
authors.identifier: http://orcid.org/0000-0002-3750-9615
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020531:Subthalamic Nucleus / Q000166:cytology* / Q000254:growth & development
chemical_list: D018683:Excitatory Amino Acid Agents; D018691:Excitatory Amino Acid Antagonists; C464436:NR2D NMDA receptor; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C056723:FG 9041
keywords: GluN2B; GluN2D; NMDA; excitatory synapse; glutamate receptor; subthalamic nucleus