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Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses

A Corrigendum to this article was published on 21 June 2001

Abstract

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.

References

  1. Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).

    Article  ADS  CAS  Google Scholar 

  2. Caulfield, M. P. & Brown, D. A. Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br. J. Pharmacol. 106, 231–232 (1992).

    Article  CAS  Google Scholar 

  3. Mackie, K. & Hille, B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc. Natl Acad. Sci. USA 89, 3825–3829 (1992).

    Article  ADS  CAS  Google Scholar 

  4. Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87, 1932–1936 (1990).

    Article  ADS  CAS  Google Scholar 

  5. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    Article  ADS  CAS  Google Scholar 

  6. Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997).

    Article  ADS  CAS  Google Scholar 

  7. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994).

    Article  ADS  CAS  Google Scholar 

  8. Di Marzo, V., Melck, D., Bisogno, T. & De Petrocellis, L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21, 521–528 (1998).

    Article  CAS  Google Scholar 

  9. Tsou, K., Mackie, K., Sañudo-Peña, M. C. & Walker, J. M. Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation. Neuroscience 93, 969–975 (1999).

    Article  CAS  Google Scholar 

  10. Katona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999).

    Article  CAS  Google Scholar 

  11. Hajos, N. et al. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur. J. Neurosci. 12, 3239–3249 (2000).

    Article  CAS  Google Scholar 

  12. Hoffman, A. F. & Lupica, C. R. Mechanisms of cannabinoid inhibition of GABA(A) synaptic transmission in the hippocampus. J. Neurosci. 20, 2470–2479 (2000).

    Article  CAS  Google Scholar 

  13. Pitler, T. A. & Alger, B. E. Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells. J. Neurosci. 12, 4122–4132 (1992).

    Article  CAS  Google Scholar 

  14. Lenz, R. A., Wagner, J. J. & Alger, B. E. N- and L-type calcium channel involvement in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells. J. Physiol. 512, 61–73 (1998).

    Article  CAS  Google Scholar 

  15. Alger, B. E. et al. Retrograde signalling in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells. J. Physiol. 496, 197–209 (1996).

    Article  CAS  Google Scholar 

  16. Morishita, W. & Alger, B. E. Sr2+ supports depolarization-induced suppression of inhibition and provides new evidence for a presynaptic expression mechanism in rat hippocampal slices. J. Physiol. 505, 307–317 (1997).

    Article  CAS  Google Scholar 

  17. Pitler, T. A. & Alger, B. E. Depolarization-induced suppression of GABAergic inhibition in rat hippocampal pyramidal cells: G protein involvement in a presynaptic mechanism. Neuron 13, 1447–1455 (1994).

    Article  CAS  Google Scholar 

  18. Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094–1097 (1997).

    Article  CAS  Google Scholar 

  19. Piomelli, D. et al. Structural determinants for recognition and translocation by the anandamide transporter. Proc. Natl Acad. Sci. USA 96, 5802–5807 (1999).

    Article  ADS  CAS  Google Scholar 

  20. Binz, T. et al. Proteolysis of SNAP-25 by types E and A botulinal neurotoxins. J. Biol. Chem. 269, 1617–1620 (1994).

    CAS  PubMed  Google Scholar 

  21. Leung, S. M., Chen, D., DasGupta, B. R., Whiteheart, S. W. & Apodaca, G. SNAP-23 requirement for transferrin recycling in Streptolysin-O-permeabilized Madin-Darby canine kidney cells. J. Biol. Chem. 273, 17732–17741 (1998).

    Article  CAS  Google Scholar 

  22. Weber, T. et al. SNAREpins: minimal machinery for membrane fusion. Cell 92, 759–772 (1998).

    Article  CAS  Google Scholar 

  23. Lledo, P. M., Zhang, X., Südhof, T. C., Malenka, R. C. & Nicoll, R. A. Postsynaptic membrane fusion and long-term potentiation. Science 279, 399–403 (1998).

    Article  ADS  CAS  Google Scholar 

  24. Lüscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649–658 (1999).

    Article  Google Scholar 

  25. Morishita, W., Kirov, S. A. & Alger, B. E. Evidence for metabotropic glutamate receptor activation in the induction of depolarization-induced suppression of inhibition in hippocampal CA1. J. Neurosci. 18, 4870–4882 (1998).

    Article  CAS  Google Scholar 

  26. Morishita, W. & Alger, B. E. Differential effects of the group II mGluR agonist, DCG-IV, on depolarization-induced suppression of inhibition in hippocampal CA1 and CA3 neurons. Hippocampus 10, 261–268 (2000).

    Article  CAS  Google Scholar 

  27. Vincent, P. & Marty, A. Neighboring cerebellar Purkinje cells communicate via retrograde inhibition of common presynaptic interneurons. Neuron 11, 885–893 (1993).

    Article  CAS  Google Scholar 

  28. Cash, S., Zucker, R. S. & Poo, M. M. Spread of synaptic depression mediated by presynaptic cytoplasmic signaling. Science 272, 998–1001 (1996).

    Article  ADS  CAS  Google Scholar 

  29. Wigström, H. & Gustafsson, B. Facilitation of hippocampal long-lasting potentiation by GABA antagonists. Acta Physiol. Scand. 125, 159–172 (1985).

    Article  Google Scholar 

  30. Brody, D. L. & Yue, D. T. Relief of G-protein inhibition of calcium channels and short-term synaptic facilitation in cultured hippocampal neurons. J. Neurosci. 20, 889–898 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

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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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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