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Voltage drives diverse endocannabinoid signals to mediate striatal microcircuit-specific plasticity

Nature Neuroscience volume 16, pages 1275–1283 (2013)Cite this article

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Abstract

The dorsolateral striatum and cannabinoid type 1 receptor (CB1) signaling mediate habitual action learning, which is thought to require a balance of activity in the direct and indirect striatal output pathways. However, very little is known about how the high CB1–expressing striatal inhibitory microcircuitry might contribute to long-term plasticity capable of sculpting direct and indirect pathway output. Using optogenetic and molecular interrogation of striatal GABAergic microcircuits, we examined voltage-dependent long-term depression of inhibitory synapses (iLTD) onto mouse and rat medium spiny projection neurons (MSNs). The observed iLTD involved recruitment of different endocannabinoid types and showed both presynaptic and postsynaptic selectivity for MSN subtypes, ultimately resulting in a powerful disinhibition of direct pathway MSNs. These results suggest a new role for voltage states in gating circuit-specific forms of synaptic plasticity and illuminate possible circuit dynamics underlying action control.

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Figure 1: State-dependent endocannabinoid (eCB)-mediated forms of inhibitory long-term depression (iLTD) at striatal inhibitory synapses.
Figure 2: Differential eCB signaling mediates up and down state forms of iLTD.
Figure 3: Up-state iLTD is output pathway nonspecific, whereas down-state iLTD is specific to direct pathway MSNs.
Figure 4: Optogenetic targeting of RGS9-expressing MSNs or striatal PV-expressing FSIs.
Figure 5: The MSN-MSN synapse contributes to both up- and down-state iLTD, whereas the FSI-MSN synapse solely contributes to down-state iLTD.
Figure 6: Cre-mediated CB1 deletion effects on state-dependent iLTD.
Figure 7: Stimulation and voltage oscillation timing-dependent iLTD.

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Acknowledgements

We would like to thank B. Lutz (Institute of Molecular Biology Mainz) and G. Marsicano (Institut National de la Santé et de la Recherche Médicale Bordeaux) for generously providing the Cnr1loxP/loxP mouse, and P. Pacher (National Institute on Alcohol Abuse and Alcoholism) for providing FAAH knockout mice.

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Authors and Affiliations

  1. Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland, USA

    Brian N Mathur & David M Lovinger

  2. Department of Morphological Neural Science, Graduate School of Medicine, Kumamoto University, Honjo, Kumamoto, Japan

    Chiyoko Tanahira & Nobuaki Tamamaki

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Contributions

B.N.M. and D.M.L. designed the experiments. B.N.M. performed the experiments and analyzed the data. C.T. and N.T. generated Pvalb-Cre and CAG-mRFP-GFP mouse lines. B.N.M. and D.M.L. wrote the manuscript.

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Correspondence to David M Lovinger.

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The authors declare no competing financial interests.

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Mathur, B., Tanahira, C., Tamamaki, N. et al. Voltage drives diverse endocannabinoid signals to mediate striatal microcircuit-specific plasticity. Nat Neurosci 16, 1275–1283 (2013). https://doi.org/10.1038/nn.3478

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