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The Journal of Neuroscience, March 15, 2006, 26(11):2914-2922; doi:10.1523/JNEUROSCI.5326-05.2006
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Neurobiology of Disease
A Critical Interaction between NR2B and MAGUK in L-DOPA Induced Dyskinesia
Fabrizio Gardoni,1 * Barbara Picconi,2 * Veronica Ghiglieri,2 Federica Polli,1 Vincenza Bagetta,2 Giorgio Bernardi,2,3 Flaminio Cattabeni,1 Monica Di Luca,1 andPaolo Calabresi2,4 1Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy, 2Laboratorio di Neurofisiologia, Fondazione Santa Lucia, Instituto di Ricovero e Cura a Carattere Scientifico, Centro Europeo di Ricerca sul Cervello, 00143 Rome, Italy, 3Clinica Neurologica, Department of Neuroscience, University of Rome Tor Vergata, 00133 Rome, Italy, and 4Clinica Neurologica, Università di Perugia, Ospedale Silvestrini, 06156 Perugia, Italy
Correspondence should be addressed to Paolo Calabresi, Clinica Neurologica, Dipartimento di Specialità Medico Chirurgiche e Sanità Pubblica, Università di Perugia, 06156 Perugia, Italy. Email: calabre{at}unipg.it
Abnormal function of NMDA receptor has been suggested to be correlated with the pathogenesis of Parkinson’s disease (PD) as well as with the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Here we show that NMDA receptor NR2 subunits display specific alterations of their subcellular distribution in striata from unilateral 6-hydroxydopamine-lesioned, L-DOPA-treated dyskinetic, and L-DOPA-treated nondyskinetic rats. Dyskinetic animals have significantly higher levels of NR2A subunit in the postsynaptic compartment than all other experimental groups, whereas NR2B subunit shows a significant reduction in both dopamine-denervated and dyskinetic rats. These events are paralleled by profound modifications of NMDA receptor NR2B subunit association with interacting elements, i.e., members of the membrane-associated guanylate kinase (MAGUK) protein family postsynaptic density-95, synapse-associated protein-97 and synapse-associated protein-102. Treatment of nondyskinetic animals with a synthetic peptide (TAT2B) able to affect NR2B binding to MAGUK proteins as well as synaptic localization of this subunit in nondyskinetic rats was sufficient to induce a shift of treated rats toward a dyskinetic motor behavior. These data indicate abnormal NR2B redistribution between synaptic and extrasynaptic membranes as an important molecular disturbance of the glutamatergic synapse involved in L-DOPA-induced dyskinesia.
Key words: Parkinson’s disease; dyskinesia; 6-OHDA; NMDA receptor; MAGUK; rat
Received July 14, 2005; revised Jan. 20, 2006; accepted Jan. 23, 2006.
Correspondence should be addressed to Paolo Calabresi, Clinica Neurologica, Dipartimento di Specialità Medico Chirurgiche e Sanità Pubblica, Università di Perugia, 06156 Perugia, Italy. Email: calabre{at}unipg.it
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