NMDA receptor GluN2A/GluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: from experimental models to patients.

Manuela Mellone, Jennifer Stanic, Ledia F. Hernandez, Elena Iglesias, Elisa Zianni, Annalisa Longhi, Annick Prigent, Barbara Picconi, Paolo Calabresi, Etienne C. Hirsch, Jose A. Obeso, Monica Di Luca, Fabrizio Gardoni
Front. Cell. Neurosci.. 2015-07-06; 9:
DOI: 10.3389/fncel.2015.00245

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Mellone M(1), Stanic J(1), Hernandez LF(2), Iglesias E(2), Zianni E(1), Longhi A(1), Prigent A(3), Picconi B(4), Calabresi P(5), Hirsch EC(3), Obeso JA(2), Di Luca M(1), Gardoni F(1).

Author information:
(1)Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano Milano, Italy.
(2)Movement Disorders Group, Neurosciences Division, Center for Applied Medical Research (CIMA), Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), University of Navarra Pamplona, Spain.
(3)Inserm, U 1127 Paris, France ; CNRS, UMR 7225 Paris, France ; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127 Paris, France ; Institut du Cerveau et de la Moelle Épinière, ICM Paris, France.
(4)Fondazione Santa Lucia, IRCCS Rome, Italy.
(5)Fondazione Santa Lucia, IRCCS Rome, Italy ; Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, Localitá, Sant’Andrea delle Fratte Perugia, Italy.

Levodopa-induced dyskinesias (LIDs) are major complications in the
pharmacological management of Parkinson’s disease (PD). Abnormal glutamatergic
transmission in the striatum is considered a key factor in the development of
LIDs. This work aims at: (i) characterizing N-methyl-D-aspartate (NMDA) receptor
GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models
of LIDs as well as in dyskinetic PD patients; and (ii) validating the potential
therapeutic effect of a cell-permeable peptide (CPP) interfering with GluN2A
synaptic localization on the dyskinetic behavior of these experimental models of
LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing
NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as
well as in post-mortem tissue from dyskinetic PD patients. The modulation of
synaptic NMDA receptor composition by a cell-permeable peptide interfering with
GluN2A subunit interaction with the scaffolding protein postsynaptic density
protein 95 (PSD-95) leads to a reduction in the dyskinetic motor behavior in the
two animal models of LIDs. Our results indicate that targeting synaptic NMDA
receptor subunit composition may represent an intriguing therapeutic approach
aimed at ameliorating levodopa motor side effects.

Auteurs Bordeaux Neurocampus