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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 and Paolo Calabresi^2,4

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

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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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