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Direct and indirect pathways of basal ganglia: a critical reappraisal

Abstract

The basal ganglia are subcortical nuclei controlling voluntary actions and have been implicated in Parkinson's disease (PD). The prevailing model of basal ganglia function states that two circuits, the direct and indirect pathways, originate from distinct populations of striatal medium spiny neurons (MSNs) and project to different output structures. These circuits are believed to have opposite effects on movement. Specifically, the activity of direct pathway MSNs is postulated to promote movement, whereas the activation of indirect pathway MSNs is hypothesized to inhibit it. Recent findings have revealed that this model might not fully account for the concurrent activation of both pathways during movement. Accordingly, we propose a model in which intrastriatal connections are critical and the two pathways are structurally and functionally intertwined. Thus, all MSNs might either facilitate or inhibit movement depending on the form of synaptic plasticity expressed at a certain moment. In PD, alterations of dopamine-dependent synaptic plasticity could alter this coordinated activity.

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Figure 1: Schematic representation of the direct/indirect pathway classical model in the physiological condition and in Parkinson's disease.

Kim Caesar/Nature Publishing Group

Figure 2: Signaling pathways downstream of D1-like and D1-D2 heteromer receptor activation.

Kim Caesar/Nature Publishing Group

Figure 3: Role of MSNs and cholinergic interneurons in the production and functions of endocannabinoids in the striatum.

Kim Caesar/Nature Publishing Group

Figure 4: Integrative hypothesis for the role of striatal circuits in controlling motor activity in the physiological condition and in Parkinson's disease.

Kim Caesar/Nature Publishing Group

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Acknowledgements

We thank A. Pisani for reading the manuscript and for critical discussion. This work was supported by Progetto di Ricerca di Interesse Nazionale (PRIN) 2011 2010AHHP5H (to P.C.) and Progetto del Ministero della Salute, Giovani Ricercatori (GR-2008-1142336 to B.P.; GR-2010-2316671 to V.G.).

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Correspondence to Paolo Calabresi.

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P.C. serves as an editorial board member of Lancet Neurology, The Journal of Neuroscience, Movement Disorders and Synapse, and receives research support from Bayer Schering, Biogen, Boehringer Ingelheim, Eisai, Merck Sharp & Dohme, Novartis, Lundbeck, Sanofi-Aventis, Sigma-Tau, UCB Pharma, Ricerca Corrente IRCCS, Ricerca Finalizzata IRCCS (European Community Grants SYNSCAFF and REPLACES), the Italian Minister of Health, and Agenzia Italiana del Farmaco.

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Calabresi, P., Picconi, B., Tozzi, A. et al. Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat Neurosci 17, 1022–1030 (2014). https://doi.org/10.1038/nn.3743

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