Distinct levels of dopamine denervation differentially alter striatal synaptic plasticity and NMDA receptor subunit composition.
A correct interplay between dopamine (DA) and glutamate is essential for corticostriatal synaptic plasticity and motor activity. In an experimental model of Parkinson's disease (PD) obtained in rats, the complete depletion of striatal DA, mimicking advanced stages of the disease, results in the loss of both forms of striatal plasticity: long-term potentiation (LTP) and long-term depression (LTD). However, early PD stages are characterized by an incomplete reduction in striatal DA levels. The mechanism by which this incomplete reduction in DA level affects striatal synaptic plasticity and glutamatergic synapses is unknown. Here we present a model of early PD in which a partial denervation, causing mild motor deficits, selectively affects NMDA-dependent LTP but not LTD and dramatically alters NMDA receptor composition in the postsynaptic density. Our findings show that DA decrease influences corticostriatal synaptic plasticity depending on the level of depletion. The use of the TAT2A cell-permeable peptide, as an innovative therapeutic strategy in early PD, rescues physiological NMDA receptor composition, synaptic plasticity, and motor behavior.
Fondazione Santa Lucia, Instituto di Ricovero e Cura a Carattere Scientifico, 00179 Rome, Italy.
Vincent
V
Paillé
Barbara
B
Picconi
Vincenza
V
Bagetta
Veronica
V
Ghiglieri
Carmelo
C
Sgobio
Massimiliano
M
Di Filippo
Maria T
MT
Viscomi
Carmela
C
Giampà
Francesca R
FR
Fusco
Fabrizio
F
Gardoni
Giorgio
G
Bernardi
Paul
P
Greengard
Monica
M
Di Luca
Paolo
P
Calabresi
D000818:Animals; D015153:Blotting, Western; D003714:Denervation; D004298:Dopamine / Q000502:physiology*; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005552:Forelimb / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D008845:Microinjections; D018613:Microscopy, Confocal; D019957:Motor Skills Disorders / Q000473:pathology / Q000523:psychology; D017072:Neostriatum / Q000166:cytology / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D016627:Oxidopamine; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000502:physiology*; D013378:Substantia Nigra / Q000502:physiology; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C120997:NR2A NMDA receptor; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013565:Sympatholytics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine