Abstract
Many types of neurons can release endocannabinoids that act as retrograde signals to inhibit neurotransmitter release from presynaptic terminals. Little is known, however, about the properties or role of such inhibition under physiological conditions. Here we report that brief bursts of presynaptic activity evoked endocannabinoid release, which strongly inhibited parallel fiber–to–Purkinje cell synapses in rat cerebellar slices. This retrograde inhibition was triggered by activation of either postsynaptic metabotropic or ionotropic glutamate receptors and was restricted to synapses activated with high-frequency bursts. Thus, endocannabinoids allow neurons to inhibit specific synaptic inputs in response to a burst, thereby dynamically fine-tuning the properties of synaptic integration.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Howlett, A.C. et al. International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54, 161–202 (2002).
Alger, B.E. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog. Neurobiol. 68, 247–286 (2002).
Kreitzer, A.C. & Regehr, W.G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29, 717–727 (2001).
Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001).
Wilson, R.I. & Nicoll, R.A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001).
Wilson, R.I. & Nicoll, R.A. Endocannabinoid signaling in the brain. Science 296, 678–682 (2002).
Kreitzer, A.C. & Regehr, W.G. Retrograde signaling by endocannabinoids. Curr. Opin. Neurobiol. 12, 324–330 (2002).
Llano, I., Leresche, N. & Marty, A. Calcium entry increases the sensitivity of cerebellar Purkinje cells to applied GABA and decreases inhibitory synaptic currents. Neuron 6, 565–574 (1991).
Pitler, T.A. & Alger, B.E. Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells. J. Neurosci. 12, 4122–4132 (1992).
Maejima, T., Hashimoto, K., Yoshida, T., Aiba, A. & Kano, M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31, 463–475 (2001).
Kreitzer, A.C., Carter, A.G. & Regehr, W.G. Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 34, 787–796 (2002).
Kreitzer, A.C. & Regehr, W.G. Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J. Neurosci. 21, RC174 (2001).
Varma, N., Carlson, C.C., Ledent, C. & Alger, B.E. Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J. Neurosci. 21, 1–5 (2001).
Robbe, D., Kopf, M., Remaury, A., Bockaert, J. & Manzoni, O.J. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc. Natl. Acad. Sci. USA 99, 8384–8388 (2002).
Chevaleyre, V. & Castillo, P.E. Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472 (2003).
Herkenham, M. et al. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci. 11, 563–583 (1991).
Tsou, K., Brown, S., Sanudo-Pena, M.C., Mackie, K. & Walker, J.M. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83, 393–411 (1998).
Levenes, C., Daniel, H., Soubrie, P. & Crepel, F. Cannabinoids decrease excitatory synaptic transmission and impair long-term depression in rat cerebellar Purkinje cells. J. Physiol. 510, 876–879 (1998).
Takahashi, K.A. & Linden, D.J. Cannabinoid receptor modulation of synapses received by cerebellar Purkinje cells. J. Neurophysiol. 83, 1167–1180 (2000).
Carter, A.G. & Regehr, W.G. Prolonged synaptic currents and glutamate spillover at the parallel fiber to stellate cell synapse. J. Neurosci. 20, 4423–4434 (2000).
Merrill, E.G., Wall, P.D. & Yaksh, T.L. Properties of two unmyelinated fibre tracts of the central nervous system: lateral Lissauer tract, and parallel fibres of the cerebellum. J. Physiol. 284, 127–145 (1978).
Eccles, J.C., Ito, M. & Szentagothai, J. The Cerebellum as a Neuronal Machine, (Springer-Verlag, Heidelberg, 1967).
Zucker, R.S. & Regehr, W.G. Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002).
Regehr, W.G. Monitoring presynaptic calcium dynamics with membrane-permeant indicators. in Imaging Neurons: a Laboratory Manual (eds. Yuste, R., Lanni, F. & Konnerth, A.) 37.1–37.11 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2000).
Tanabe, Y. et al. Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. J. Neurosci. 13, 1372–1378 (1993).
Konnerth, A., Llano, I. & Armstrong, C.M. Synaptic currents in cerebellar Purkinje cells. Proc. Natl. Acad. Sci. USA 87, 2662–2665 (1990).
Baude, A. et al. The metabotropic glutamate receptor (mGluR1 alpha) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 11, 771–787 (1993).
Batchelor, A.M., Madge, D.J. & Garthwaite, J. Synaptic activation of metabotropic glutamate receptors in the parallel fibre–Purkinje cell pathway in rat cerebellar slices. Neuroscience 63, 911–915 (1994).
Neale, S.A., Garthwaite, J. & Batchelor, A.M. mGlu1 receptors mediate a post-tetanic depression at parallel fibre-Purkinje cell synapses in rat cerebellum. Eur. J. Neurosci. 14, 1313–1319 (2001).
Ross, W.N. & Werman, R. Mapping calcium transients in the dendrites of Purkinje cells from the Guinea-pig cerebellum in vitro. J. Physiol. 389, 319–336 (1987).
Tank, D.W., Sugimori, M., Connor, J.A. & Llinas, R.R. Spatially resolved calcium dynamics of mammalian Purkinje cells in cerebellar slice. Science 242, 773–776 (1988).
Miyakawa, H., Lev-Ram, V., Lasser-Ross, N. & Ross, W.N. Calcium transients evoked by climbing fiber and parallel fiber synaptic inputs in guinea pig cerebellar Purkinje neurons. J. Neurophysiol. 68, 1178–1189 (1992).
Wang, S.S., Denk, W. & Hausser, M. Coincidence detection in single dendritic spines mediated by calcium release. Nat. Neurosci. 3, 1266–1273 (2000).
Finch, E.A. & Augustine, G.J. Local calcium signalling by inositol-1,4,5-triphosphate in Purkinje cell dendrites. Nature 396, 753–756 (1998).
Takechi, H., Eilers, J. & Konnerth, A. A new class of synaptic response involving calcium release in dendritic spines. Nature 396, 757–760 (1998).
Palay, S.L. & Chan-Palay, V. Cerebellar Cortex (Springer-Verlag, New York, 1974).
Mintz, I.M., Sabatini, B.L. & Regehr, W.G. Calcium control of transmitter release at a cerebellar synapse. Neuron 15, 675–688 (1995).
Kase, M., Miller, D.C. & Noda, H. Discharges of Purkinje cells and mossy fibres in the cerebellar vermis of the monkey during saccadic eye movements and fixation. J. Physiol. 300, 539–555 (1980).
van Kan, P.L.E., Gibson, A.R. & Houk, J.C. Movement-related inputs to intermediate cerebellum of the monkey. J. Neurophysiol. 69, 74–94 (1993).
D'Angelo, E., de Filippi, G., Rossi, P. & Taglietti, V. Synaptic excitation of individual rat cerebellar granule cells in situ: evidence for the role of NMDA receptors. J. Physiol. 484, 397–413 (1995).
Lisman, J.E. Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 20, 38–43 (1997).
Batchelor, A.M. & Garthwaite, J. Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway. Nature 385, 74–77 (1997).
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).
Vincent, P. & Marty, A. Neighboring cerebellar Purkinje cells communicate via retrograde inhibition of common presynaptic interneurons. Neuron 11, 885–893 (1993).
Eilers, J., Augustine, G.J. & Konnerth, A. Subthreshold synaptic Ca2+ signalling in fine dendrites and spines of cerebellar Purkinje neurons. Nature 373, 155–158 (1995).
Denk, W., Sugimori, M. & Llinas, R. Two types of calcium response limited to single spines in cerebellar Purkinje cells. Proc. Natl. Acad. Sci. USA 92, 8279–8282 (1995).
Turrigiano, G.G. Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci. 22, 221–227 (1999).
Carlson, C.C., Wang, J. & Alger, B.E. Endocannabinoids facilitate the induction of LTP in the hippocampus. Nat. Neurosci. 5, 723–724 (2002).
Gerdeman, G.L., Ronesi, J. & Lovinger, D.M. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat. Neurosci. 5, 446–451 (2002).
Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997).
Acknowledgements
We thank M. Beierlein, D. Blitz, K. Foster, A. Kreitzer, P. Safo and M. Xu-Friedman for comments on the manuscript. This work was supported by the US National Institutes of Health (RO1 NS 32405, RO1 NS 44396 and 5 T32 NS07484-02).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Brown, S., Brenowitz, S. & Regehr, W. Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids. Nat Neurosci 6, 1048–1057 (2003). https://doi.org/10.1038/nn1126
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn1126
This article is cited by
-
Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism
Neuropsychopharmacology (2022)
-
Cannabinoids, TRPV and nitric oxide: the three ring circus of neuronal excitability
Brain Structure and Function (2020)
-
Coordinated regulation of endocannabinoid-mediated retrograde synaptic suppression in the cerebellum by neuronal and astrocytic monoacylglycerol lipase
Scientific Reports (2016)
-
Emerging Trends in Retrograde Signaling
Molecular Neurobiology (2016)
-
Weeding out bad waves: towards selective cannabinoid circuit control in epilepsy
Nature Reviews Neuroscience (2015)