Nature Neuroscience6, 501 - 506 (2003)
Published online: 31 March 2003; | doi:10.1038/nn1040
Loss of bidirectional striatal synaptic plasticity in L-DOPA−induced dyskinesia
Barbara Picconi1, 2, Diego Centonze1, 2, Kerstin Håkansson3, Giorgio Bernardi1, 2, Paul Greengard4, Gilberto Fisone3, 4, M. Angela Cenci5
& Paolo Calabresi1, 2
1
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
2
Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, Via Ardeatina 306, 00179 Rome, Italy
3
Department of Neuroscience, Karolinska Institutet, S-171 77 Stockholm, Sweden
4
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Ave., Box 296, New York, New York 10021, USA
5
Wallenberg Neuroscience Centre, Neurobiology Division, Lund University, Sölvegatan 17 223 62 Lund, Sweden
Long-term treatment with the dopamine precursor levodopa (L-DOPA) induces dyskinesia in Parkinson's disease (PD) patients. We divided hemiparkinsonian rats treated chronically with L-DOPA into two groups: one showed motor improvement without dyskinesia, and the other developed debilitating dyskinesias in response to the treatment. We then compared the plasticity of corticostriatal synapses between the two groups. High-frequency stimulation of cortical afferents induced long-term potentiation (LTP) of corticostriatal synapses in both
groups of animals. Control and non-dyskinetic rats showed synaptic depotentiation in response to subsequent low-frequency synaptic stimulation, but dyskinetic rats did not. The depotentiation seen in both L-DOPA−treated non-dyskinetic rats and intact controls was prevented by activation of the D1 subclass of dopamine receptors or inhibition of protein phosphatases. The striata of dyskinetic rats contained abnormally high levels of phospho[Thr34]-DARPP-32, an inhibitor of protein phosphatase 1. These results indicate that abnormal information storage in corticostriatal synapses is linked with the development of L-DOPA−induced dyskinesia.
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