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The role of neuroplasticity in dopaminergic therapy for Parkinson disease

Nature Reviews Neurology volume 9, pages 248–256 (2013)Cite this article

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Abstract

Dopamine replacement is a mainstay of therapeutic strategies for Parkinson disease (PD). The motor response to therapy involves an immediate improvement in motor function, known as the short-duration response (SDR), followed by a long-duration response (LDR) that develops more slowly, over weeks. Here, we review evidence in patients and animal models suggesting that dopamine-dependent corticostriatal plasticity, and retention of such plasticity in the absence of dopamine, are the mechanisms underlying the LDR. Conversely, experience-dependent aberrant plasticity that develops slowly under reduced dopamine levels could contribute substantially to PD motor symptoms before initiation of dopamine replacement therapy. We place these findings in the context of the role of dopamine in basal ganglia function and corticostriatal plasticity, and provide a new framework suggesting that therapies that enhance the LDR could be more effective than those targeting the SDR. We further propose that changes in neuroplasticity constitute a form of disease modification that is distinct from prevention of degeneration, and could be responsible for some of the unexplained disease-modifying effects of certain therapies. Understanding such plasticity could provide novel therapeutic approaches that combine rehabilitation and pharmacotherapy for treatment of neurological and psychiatric disorders involving basal ganglia dysfunction.

Key Points

  • Dopaminergic loss and therapy in Parkinson disease (PD) leads to changes in synaptic plasticity, particularly at cortiostriatal synapses

  • The motor response to dopamine therapy involves acute improvement in motor performance (short-duration response [SDR]) and a more gradual improvement in motor function (long-duration response [LDR]) that develops over weeks

  • Clinical evidence shows that the LDR is a critical component of motor response fluctuations and may be a more effective target of therapy than the SDR

  • Motor learning mediated by synaptic plasticity in the basal ganglia circuitry results in the LDR in an animal model of PD

  • Synergistic interaction between effects of physical activity and dopamine signalling contributes to the LDR

  • Enhancement of motor learning and prevention of aberrant plasticity and learned inhibitory behaviour could be a novel approach to disease modification in PD

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Figure 1: The long-duration response and short-duration response to levodopa.
Figure 2: Dopaminergic modulation of striatal cell excitability and corticostriatal plasticity.
Figure 3: Rotarod performance during and after levodopa treatment.

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Acknowledgements

The authors were supported by the NIH (NS062425 and NS070269 to X. Zhuang, NS052804 to P. Mazzoni, and NS062425 and NS064865 to U. J. Kang), the American Parkinson Disease Association (X. Zhuang and U. J. Kang), the Parkinson's Disease Foundation (P. Mazzoni), and the Michael J. Fox Foundation for Parkinson's Research (U. J. Kang).

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Authors and Affiliations

  1. Department of Neurobiology, University of Chicago Medicine and Biological Sciences, 947 South 58th Street, MC 0926, Chicago, 60637, IL, USA

    Xiaoxi Zhuang

  2. The Neurological Institute, Columbia University Medical Center, 710 West 168th Street, New York, 10032, NY, USA

    Pietro Mazzoni

  3. Department of Neurology, University of Chicago Medicine and Biological Sciences, 5841 South Maryland Avenue, MC 2030, Chicago, 60637, IL, USA

    Un Jung Kang

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  1. Xiaoxi Zhuang
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All authors contributed to researching data for the article, discussion of the article content, writing of the article and to review and/or editing of the manuscript before submission.

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Correspondence to Un Jung Kang.

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Zhuang, X., Mazzoni, P. & Kang, U. The role of neuroplasticity in dopaminergic therapy for Parkinson disease. Nat Rev Neurol 9, 248–256 (2013). https://doi.org/10.1038/nrneurol.2013.57

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