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Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models

Abstract

The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia1,2. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Imbalances between neural activity in these two pathways have been proposed to underlie the profound motor deficits observed in Parkinson's disease and Huntington's disease3,4. However, little is known about differences in cellular and synaptic properties in these circuits. Indeed, current hypotheses suggest that these cells express similar forms of synaptic plasticity5,6. Here we show that excitatory synapses onto indirect-pathway medium spiny neurons (MSNs) exhibit higher release probability and larger N-methyl-d-aspartate receptor currents than direct-pathway synapses. Moreover, indirect-pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor activation. In models of Parkinson's disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation. Administration of these drugs together in vivo reduces parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement. These findings have implications for understanding the normal functions of the basal ganglia, and also suggest approaches for the development of therapeutic drugs for the treatment of striatal-based brain disorders.

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Figure 1: Presynaptic properties of direct-pathway and indirect-pathway synapses on striatal MSNs.
Figure 2: Postsynaptic properties of direct-pathway and indirect-pathway synapses.
Figure 3: Endocannabinoid-mediated LTD is restricted to indirect-pathway synapses.
Figure 4: Pharmacological rescue of indirect-pathway LTD and motor deficits in animal models of Parkinson's disease.

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Acknowledgements

We thank W. Regehr, B. Sabatini, D. Lovinger, D. Piomelli, J. Surmeier and members of the Malenka laboratory for helpful discussions, X. W. Yang for providing BAC-transgenic mice generated by the GENSAT project, M. Xu-Friedman for providing custom Igor acquisition software, and S. Y. Lee and X. Cai for technical help. This work was supported by a Ruth L. Kirchenstein Fellowship (A.C.K.), a grant from the National Institutes of Health (R.C.M.), and a National Parkinson Foundation Individual Research Grant (R.C.M. and A.C.K.).

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Correspondence to Robert C. Malenka.

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Kreitzer, A., Malenka, R. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature 445, 643–647 (2007). https://doi.org/10.1038/nature05506

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