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Hyperkinetic disorders and loss of synaptic downscaling

Abstract

Recent clinical and preclinical studies have shown that hyperkinetic disorders such as Huntington's disease, dystonia and l-DOPA-induced dyskinesia in Parkinson's disease are all characterized by loss of the ability to reverse synaptic plasticity and an associated increase in the excitability of excitatory neuronal inputs to a range of cortical and subcortical brain areas. Moreover, these changes have been detected in humans with hyperkinetic disorders either via direct recordings from implanted deep brain electrodes or noninvasively using transcranial magnetic stimulation. Here we discuss the mechanisms underlying the loss of bidirectional plasticity and the possibility that future interventions could be devised to reverse these changes in patients with hyperkinetic movement disorders.

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Figure 1: Alterations of striatal synaptic plasticity in three experimental models of hyperkinetic disorders.
Figure 2: Schematic representation of the common abnormalities in cAMP–PKA pathway downstream of dopamine D1 and adenosine A2A receptors in striatal spiny neurons in experimental models of hyperkinetic disorders.

Kim Caesar/Nature Publishing Group

Figure 3: Effects of TMS on motor cortex plasticity in PD with LID.
Figure 4: Effects of DBS on subcortical synaptic plasticity in dystonia and in PD with LID.
Figure 5: Hypothetical representation of the link between human plasticity and synaptic changes in in vitro models.

Kim Caesar/Nature Publishing Group

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Acknowledgements

This work was supported by grants from Progetto di Ricerca di Interesse Nazionale (PRIN) 2011 (prot. 2010AHHP5H) (to A.P. and P.C.), Fondazione Cariplo, grant no. 2014-0660 (to P.C.), Italian Ministry of Education, University and Research, FIRB Call Program “Futuro in Ricerca” Project no. RBFR13S4LE_002 (to V.G.) and from the Italian Ministry of Health, Ricerca Finalizzata and Giovani Ricercatori (GR-2010-2316671 to V.G., RF-2013-02357386 to B.P. and RF-2013-02356215 to P.C.).

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A.P., J.A.O., J.R. and P.C. conceived and planned the Perspective. P.C. wrote the first draft of the Perspective. All authors contributed to the discussion and edited the Perspective. B.P. and V.G. edited the manuscript and made the figures.

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P.C. receives research support from Bayer Schering, Biogen, Merck Sharp & Dohme, Sanofi-Aventis, and UCB Pharma.

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Calabresi, P., Pisani, A., Rothwell, J. et al. Hyperkinetic disorders and loss of synaptic downscaling. Nat Neurosci 19, 868–875 (2016). https://doi.org/10.1038/nn.4306

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