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Endocannabinoid signaling depends on the spatial pattern of synapse activation

Nature Neuroscience volume 8, pages 776–781 (2005)Cite this article

Abstract

The brain's endocannabinoid retrograde messenger system decreases presynaptic transmitter release, but its physiological function is uncertain. We show that endocannabinoid signaling is absent when spatially dispersed synapses are activated on rodent cerebellar Purkinje cells but that it reduces presynaptic glutamate release when nearby synapses are active. This switching of signaling according to the spatial pattern of activity is controlled by postsynaptic type I metabotropic glutamate receptors, which are activated disproportionately when glutamate spillover between synapses produces synaptic crosstalk. When spatially distributed synapses are activated, endocannabinoid inhibition of transmitter release can be rescued by inhibiting glutamate uptake to increase glutamate spillover. Endocannabinoid signaling initiated by type I metabotropic glutamate receptors is a homeostatic mechanism that detects synaptic crosstalk and downregulates glutamate release in order to promote synaptic independence.

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Figure 1: Endocannabinoid-mediated plasticity seen for activation of nearby synapses is absent when stimulating spatially dispersed synapses.
Figure 2: Absence of endocannabinoid signalling when activating spatially dispersed synapses results from mGluR1 activation depending on synaptic crosstalk.
Figure 3: Glutamate spillover mediates synaptic crosstalk detection by mGluR1.
Figure 4: Endocannabinoid-mediated plasticity is rescued for stimulation of spatially dispersed synapses by enhancing glutamate spillover, and inhibits glutamate release sufficiently to abolish crosstalk activation of mGluR1.

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References

  1. Marr, D. A theory of cerebellar cortex. J. Physiol. (Lond.) 202, 437–470 (1969).

    Article  CAS  Google Scholar 

  2. Ito, M. Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol. Rev. 81, 1143–1195 (2001).

    Article  CAS  Google Scholar 

  3. Barbour, B. & Hausser, M. Intersynaptic diffusion of transmitter. Trends Neurosci. 20, 377–384 (1997).

    Article  CAS  Google Scholar 

  4. Marcaggi, P., Billups, D. & Attwell, D. The role of glial glutamate transporters in maintaining the independent operation of juvenile mouse cerebellar parallel fiber synapses. J. Physiol. (Lond.) 552, 89–107 (2003).

    Article  CAS  Google Scholar 

  5. Barbour, B. Synaptic currents evoked in Purkinje cells by stimulating individual granule cells. Neuron 11, 759–769 (1993).

    Article  CAS  Google Scholar 

  6. Wilson, R.I. & Nicoll, R.A. Endocannabinoid signaling in the brain. Science 296, 678–682 (2002).

    Article  CAS  Google Scholar 

  7. Kreitzer, A.C. & Regehr, W.G. Retrograde signaling by endocannabinoids. Curr. Opin. Neurobiol. 12, 324–330 (2002).

    Article  CAS  Google Scholar 

  8. Coutinho, V., Mutoh, H. & Knöpfel, T. Functional topology of the mossy fiber-granule cell-Purkinje cell system revealed by imaging of intrinsic fluorescence in mouse cerebellum. Eur. J. Neurosci. 20, 740–748 (2004).

    Article  CAS  Google Scholar 

  9. Batchelor, A.M. & Garthwaite, J. Novel synaptic potentials in cerebellar Purkinje cells: probable mediation by metabotropic glutamate receptors. Neuropharmacology 32, 11–20 (1993).

    Article  CAS  Google Scholar 

  10. Tempia, F., Miniaci, M.C., Anchisi, D. & Strata, P. Postsynaptic current mediated by metabotropic glutamate receptors in cerebellar Purkinje cells. J. Neurophysiol. 80, 520–528 (1998).

    Article  CAS  Google Scholar 

  11. Brown, S.P., Brenowitz, S.D. & Regehr, W.G. Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids. Nat. Neurosci. 6, 1048–1057 (2003).

    Article  CAS  Google Scholar 

  12. Levenes, C., Daniel, H. & Crepel, F. Retrograde modulation of transmitter release by postsynaptic subtype 1 metabotropic glutamate receptors in the rat cerebellum. J. Physiol. (Lond.) 537, 125–140 (2001).

    Article  CAS  Google Scholar 

  13. Kreitzer, A.C. & Regehr, W. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29, 717–727 (2001).

    Article  CAS  Google Scholar 

  14. Maejima, T., Hashimoto, K., Yoshida, T., Alba, A. & Kano, M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31, 463–475 (2001).

    Article  CAS  Google Scholar 

  15. Brenowitz, S.D. & Regehr, W.G. Associative short-term synaptic plasticity mediated by endocannabinoids. Neuron 45, 419–431 (2005).

    Article  CAS  Google Scholar 

  16. Eccles, J.C., Llinas, R. & Sasaki, K. The mossy fiber-granule cell relay in the cerebellum and its inhibition by Golgi cells. Exp. Brain Res. 1, 82–101 (1966).

    CAS  Google Scholar 

  17. Kim, S.J., Kim, Y.S., Yuan, J.P., Petralia, R.S., Worley, P.F. & Linden, D.J. Activation of the TRPC1 cation channel by metabotropic glutamate receptor mGluR1. Nature 426, 285–291 (2003).

    Article  CAS  Google Scholar 

  18. Takechi, H., Eilers, J. & Konnerth, A. A new class of synaptic response involving calcium release in dendritic spines. Nature 396, 757–760 (1998).

    Article  CAS  Google Scholar 

  19. Batchelor, A.M. & Garthwaite, J. Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway. Nature 385, 74–77 (1997).

    Article  CAS  Google Scholar 

  20. Kushmerick, C. et al. Retroinhibition of presynaptic Ca2+ currents by endocannabinoids released via postsynaptic mGluR activation at a calyx synapse. J. Neurosci. 24, 5955–5965 (2004).

    Article  CAS  Google Scholar 

  21. Brasnjo, G. & Otis, T.S. Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression. Neuron 31, 607–616 (2001).

    Article  CAS  Google Scholar 

  22. Diana, M.A., Levenes, C., Mackie, K. & Marty, A. Short-term retrograde inhibition of GABAergic synaptic currents in rat Purkinje cells is mediated by endogenous cannabinoids. J. Neurosci. 22, 200–208 (2002).

    Article  CAS  Google Scholar 

  23. Brenowitz, S.D. & Regehr, W.G. Calcium dependence of retrograde inhibition by endocannabinoids at synapses onto Purkinje cells. J. Neurosci. 23, 6373–6384 (2003).

    Article  CAS  Google Scholar 

  24. Sims, R.E. & Hartell, N.A. Differences in transmission properties and susceptibility to long-term depression reveal functional specialization of ascending axon and parallel fiber synapses to Purkinje cells. J. Neurosci. 25, 3246–3257 (2005).

    Article  CAS  Google Scholar 

  25. Neale, S.A., Garthwaite, J. & Batchelor, A.M. Metabotropic glutamate receptor subtypes modulating neurotransmission at parallel fiber-Purkinje cell synapses in rat cerebellum. Neuropharmacology 41, 42–49 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Tanaka for providing the knockout mice, and B. Barbour, A. Gibb, D. Rossi, A. Silver and M. Hamann for comments on the manuscript. Supported by the European Union, the Wellcome Trust and a Wolfson-Royal Society award.

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  1. Department of Physiology, University College London, Gower Street, London, WC1E 6BT, UK

    Païkan Marcaggi & David Attwell

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  1. Païkan Marcaggi
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Correspondence to Païkan Marcaggi.

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Marcaggi, P., Attwell, D. Endocannabinoid signaling depends on the spatial pattern of synapse activation. Nat Neurosci 8, 776–781 (2005). https://doi.org/10.1038/nn1458

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