Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses

A Corrigendum to this article was published on 21 June 2001


Marijuana affects brain function primarily by activating the G-protein-coupled cannabinoid receptor-1 (CB1)1,2,3, which is expressed throughout the brain at high levels4. Two endogenous lipids, anandamide and 2-arachidonylglycerol (2-AG), have been identified as CB1 ligands5,6. Depolarized hippocampal neurons rapidly release both anandamide and 2-AG in a Ca2+-dependent manner6,7,8. In the hippocampus, CB1 is expressed mainly by GABA (γ-aminobutyric acid)-mediated inhibitory interneurons, where CB1 clusters on the axon terminal9,10,11. A synthetic CB1 agonist depresses GABA release from hippocampal slices10,12. These findings indicate that the function of endogenous cannabinoids released by depolarized hippocampal neurons might be to downregulate GABA release. Here we show that the transient suppression of GABA-mediated transmission that follows depolarization of hippocampal pyramidal neurons13 is mediated by retrograde signalling through release of endogenous cannabinoids. Signalling by the endocannabinoid system thus represents a mechanism by which neurons can communicate backwards across synapses to modulate their inputs.

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Figure 1: DSI requires endogenous cannabinoids.
Figure 2: DSI is mimicked and occluded by blocking uptake of endogenous CB1 ligands.
Figure 3: DSI and a CB1 agonist suppress IPSCs by the same mechanism.
Figure 4: The postsynaptic properties of DSI are consistent with cannabinoids but inconsistent with a classical neurotransmitter.
Figure 5: The retrograde signal in DSI can disinhibit nearby neurons.


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We thank J. S. Isaacson and E. Schnell for suggesting a role for cannabinoids in DSI; R. S. Zucker for technical advice in the calcium uncaging experiments; and R. H. Scheller and Y. A. Chen for the gift of recombinant BTE light chain and SNAP-25. We are grateful for the comments on the manuscript contributed by D. S. Bredt, D. R. Copenhagen, R. H. Edwards, M. Frerking, D. Schmitz and M. P. Stryker. R.I.W. is supported by a National Science Foundation Graduate Research Fellowship. R.A.N. is a member of the Keck Center for Integrative Neuroscience and the Silvio Conte Center for Neuroscience Research. R.A.N. was supported by grants from the National Institutes of Health and the Bristol-Myers Squibb Corporation.

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Correspondence to Roger A. Nicoll.

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Wilson, R., Nicoll, R. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001). https://doi.org/10.1038/35069076

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