title: NMDA receptor GluN2A/GluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: from experimental models to patients.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano Milano, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mellone
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano Milano, Italy.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stanic
authors.affiliation: 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.
authors.forename: Ledia F
authors.initials: LF
authors.lastname: Hernandez
authors.affiliation: 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Iglesias
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Zianni
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano Milano, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Longhi
authors.affiliation: 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.
authors.forename: Annick
authors.initials: A
authors.lastname: Prigent
authors.affiliation: Fondazione Santa Lucia, IRCCS Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.affiliation: 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.
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.affiliation: 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.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Obeso
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano Milano, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
keywords: 6-OHDA rat model; MPTP monkey model; NMDA receptor; Parkinson’s disease; cell-permeable peptides; levodopa-induced dyskinesias; patients; striatum