GluN2D-containing NMDA receptors inhibit neurotransmission in the mouse striatum through a cholinergic mechanism: implication for Parkinson's disease.
The GluN2 subunits that compose NMDA receptors (NMDARs) determine functional and pharmacological properties of the receptor. In the striatum, functions and potential dysfunctions of NMDARs attributed to specific GluN2 subunits have not been clearly elucidated, although NMDARs play critical roles in the interactions between glutamate and dopamine. Through the use of amperometry and field potential recordings in mouse brain slices, we found that NMDARs that contain the GluN2D subunit contribute to NMDA-induced inhibition of evoked dopamine release and of glutamatergic neurotransmission in the striatum of control mice. Inhibition is likely mediated through increased firing in cholinergic interneurons, which were shown to express GluN2D. Indeed, NMDA-induced inhibition of both dopamine release and glutamatergic neurotransmission is reduced in the presence of muscarinic receptor antagonists and is mimicked by a muscarinic receptor agonist. We have also examined whether this function of GluN2D-containing NMDARs is altered in a mouse model of Parkinson's disease. We found that the inhibitory role of GluN2D-containing NMDARs on glutamatergic neurotransmission is impaired in the 6-hydroxydopamine lesioned striatum. These results identify a role for GluN2D-containing NMDARs and adaptive changes in experimental Parkinsonism. GluN2D might constitute an attractive target for the development of novel pharmacological tools for therapeutic intervention in Parkinson's disease.
Department of Physiology and Pharmacology, Section of Molecular Neurophysiology, The Karolinska Institute, Stockholm, Sweden.
Xiaoqun
X
Zhang
Ze-Jun
ZJ
Feng
Karima
K
Chergui
D000109:Acetylcholine / Q000502:physiology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology*; D003864:Depression, Chemical; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012636:Secretory Rate / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; C464436:NR2D NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016627:Oxidopamine; D000109:Acetylcholine; D004298:Dopamine
GluN2D; NMDA receptor; Parkinson's disease; acetylcholine; dopamine; glutamate