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Loss of bidirectional striatal synaptic plasticity in L-DOPA–induced dyskinesia

Abstract

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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Figure 1: Behavioral testing to divide L-DOPA–treated rats into dyskinetic and non-dyskinetic groups.
Figure 2: Chronic L-DOPA treatment of Parkinsonian rats restores LTP and blocks depotentiation in dyskinetic rats.
Figure 3: Pharmacological characterization of LFS-induced depotentiation in striatal spiny neurons.
Figure 4: DARPP-32 phosphorylation at Thr34 is enhanced in Parkinsonian dyskinetic rats.

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Acknowledgements

The authors wish to thank M. Tolu for technical assistance. This work was supported by a CNR Neurobiotecnologie–FISR and a Telethon grant GGP02035 (P.C.), by the Swedish Research Council (G.F. and M.A.C.), by National Institutes of Health grants MH40899 and DA10044 (P.G.) and by The Kocks′ Foundation and The Swedish Association of the Neurologically Disabled (M.A.C.).

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Correspondence to Paolo Calabresi.

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Picconi, B., Centonze, D., Håkansson, K. et al. Loss of bidirectional striatal synaptic plasticity in L-DOPA–induced dyskinesia. Nat Neurosci 6, 501–506 (2003). https://doi.org/10.1038/nn1040

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