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Polymodal activation of the endocannabinoid system in the extended amygdala


The reason why neurons synthesize more than one endocannabinoid (eCB) and how this is involved in the regulation of synaptic plasticity in a single neuron is not known. We found that 2-arachidonoylglycerol (2-AG) and anandamide mediate different forms of plasticity in the extended amygdala of rats. Dendritic L-type Ca2+ channels and the subsequent release of 2-AG acting on presynaptic CB1 receptors triggered retrograde short-term depression. Long-term depression was mediated by postsynaptic mGluR5-dependent release of anandamide acting on postsynaptic TRPV1 receptors. In contrast, 2-AG/CB1R-mediated retrograde signaling mediated both forms of plasticity in the striatum. These data illustrate how the eCB system can function as a polymodal signal integrator to allow the diversification of synaptic plasticity in a single neuron.

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Figure 1: Single BNST neurons express both short-term and long-term eCB-dependent depression.
Figure 2: Production of 2-AG mediates STD through L-type Ca2+ channels in the BNST.
Figure 3: Anandamide and TRPV1 mediates LTD in the BNST.
Figure 4: Subcellular and synaptic localization of mGluR5, Cav1.2, CB1R and TRPV1 in BNST.
Figure 5: 2-AG mediates both STD and LTD in the striatum.


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The authors thank N. Stella, M. Sepers and P. Chavis for critical reading of the manuscript, and R. Martinez for invaluable help in setting up the Manzoni laboratory. Work in the Manzoni laboratory was supported by INSERM, Agence National pour la Recherche Neurosciences (Neurologie et Psychiatrie ANR-06-NEURO-043-01) and Région Aquitaine. N.P. was supported by Basque Country Government Postdoctoral grant BFI05.185 and by a Basque Country University grant for PhD Researcher's Specialization. P.G. was supported by Basque Country Government grant GIC07/70-IT-432-07, by Ministerio de Ciencia e Innovación (SAF2009-07065) and by “Red de Trastornos Adictivos,” RETICS, Instituto de Salud Carlos III, MICINN, grant RD07/0001/2001. Y.C. was supported by the Neuroscience School of Paris, Agence National pour la Recherche Neurosciences “Mobil,” INSERM and College de France.

Author information




N.P. performed the BNST electrophysiology and all of the electron microscopy experiments, conducted the data analyses, and contributed to the design of the experiments. Y.C. performed the striatum electrophysiology experiments and conducted the data analyses. O.L. and M.L. performed part of the BNST electrophysiology and conducted the data analyses. F.G. introduced the BNST preparation to the laboratory. P.G. designed the electron microscopy experiments and wrote the manuscript. L.V. designed the striatal electrophysiology experiments and wrote the manuscript. O.J.M. contributed to the design of all the experiments, supervised the project and wrote the manuscript.

Corresponding authors

Correspondence to Laurent Venance or Pedro Grandes or Olivier J Manzoni.

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The authors declare no competing financial interests.

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Puente, N., Cui, Y., Lassalle, O. et al. Polymodal activation of the endocannabinoid system in the extended amygdala. Nat Neurosci 14, 1542–1547 (2011).

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