NMDA receptor GluN2D subunit participates to levodopa-induced dyskinesia pathophysiology
Neurobiology of Disease. 2019-01-01; 121: 338-349
DOI: 10.1016/j.nbd.2018.09.021
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Mellone M(1), Zianni E(1), Stanic J(1), Campanelli F(2), Marino G(2), Ghiglieri V(3), Longhi A(1), Thiolat ML(4), Li Q(5), Calabresi P(6), Bezard E(7), Picconi B(8), Di Luca M(1), Gardoni F(9).
Author information:
(1)Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano – La Statale, 20133 Milano, Italy.
(2)Laboratory of Neurophysiology, Santa Lucia Foundation, IRCCS, 00100 Rome, Italy.
(3)Laboratory of Neurophysiology, Santa Lucia Foundation, IRCCS, 00100 Rome, Italy; Department of Philosophy, Human, Social and Educational Sciences, University of Perugia, 06100 Perugia, Italy.
(4)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
(5)Motac Neuroscience Ltd, Manchester, United Kingdom; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.
(6)Laboratory of Neurophysiology, Santa Lucia Foundation, IRCCS, 00100 Rome, Italy; Clinica Neurologica, Università degli studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia, Italy.
(7)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Motac Neuroscience Ltd, Manchester, United
Kingdom; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.
(8)Università San Raffaele Pisana, 00100 Rome, Italy.
(9)Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università
degli Studi di Milano – La Statale, 20133 Milano, Italy. Electronic address:
.
In the striatum, specific N-methyl-d-aspartate receptor (NMDAR) subtypes are
found in different neuronal cells. Spiny projection neurons (SPNs) are
characterized by NMDARs expressing GluN2A and GluN2B subunits, while GluN2D is
exclusively detected in striatal cholinergic interneurons (ChIs). In Parkinson’s
disease (PD), dopamine depletion and prolonged treatment with levodopa (L-DOPA)
trigger adaptive changes in the glutamatergic transmission from the cortex to the
striatum, also resulting in the aberrant function of striatal NMDARs. While
modifications of GluN2A- and GluN2B-NMDARs in SPNs have been extensively
documented, only few studies report GluN2D dysfunction in PD and no data are
available in L-DOPA-induced dyskinesia (LID). Here we investigate the
contribution of a specific NMDAR subtype (GluN2D-NMDAR) to PD and LID, and
whether this receptor could represent a candidate for future pharmacological
interventions. Our results show that GluN2D synaptic abundance is selectively
augmented in the striatum of L-DOPA-treated male parkinsonian rats displaying a
dyskinetic phenotype. This event is associated to a dramatic increase in GluN2D
binding to the postsynaptic protein scaffold PSD-95. Moreover,
immunohistochemistry and electrophysiology experiments reveal that GluN2D-NMDARs
are expressed not only by striatal ChIs but also by SPNs in dyskinetic rats.
Notably, in vivo treatment with a well-characterized GluN2D antagonist
ameliorates the severity of established dyskinesia in L-DOPA-treated animals. Our
findings support a role for GluN2D-NMDARs in LID, and they confirm that cell-type
and subunit specific modifications of NMDARs underlie the pathophysiology of LID.