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Retrograde endocannabinoid signaling in the cerebellar cortex

The Cerebellum volume 5, pages 134–145 (2006)Cite this article

Abstract

The regulation of Purkinje cell activity is important for motor behavior and motor learning. As the sole output cell of the cerebellar cortex, Purkinje cell firing is controlled by parallel fibers and climbing fiber synapses, and by inhibitory interneurons. Depolarization of Purkinje cells evokes endocannabinoid release that activates cannabinoid CB1 receptors expressed on boutons of its synaptic inputs to transiently decrease neurotransmitter release. In addition, associative activation of the excitatory inputs can liberate endocannabinoids to decrease synaptic strength for a prolonged duration. Here we review the different mechanisms of evoking endocannabinoid release and discuss the physiological role of endocannabinoids in mediating global modulation of synaptic strength, localized short-term associative plasticity and cerebellar long term depression

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References

  1. Raymond JL, Lisberger SG, Mauk MD. The cerebellum: A neuronal learning machine? Science. 1996;272(5265): 1126–31.

    PubMed  Article  CAS  Google Scholar 

  2. Palay SL, Chan-Palay V. Cerebellar cortex. New York: Springer-Verlag; 1974.

    Google Scholar 

  3. Zucker RS, Regehr WG. Short-term synaptic plasticity. Annu Rev Physiol. 2002;64:355–405.

    PubMed  Article  CAS  Google Scholar 

  4. Carey M, Lisberger S. Embarrassed, but not depressed: Eye opening lessons for cerebellar learning. Neuron. 2002;35: 223–6.

    PubMed  Article  CAS  Google Scholar 

  5. Kreitzer AC, Regehr WG. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron. 2001;29:717–27.

    PubMed  Article  CAS  Google Scholar 

  6. Maejima T, Hashimoto K, Yoshida T, Aiba A, Kano M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron. 2001;31:463–75.

    PubMed  Article  CAS  Google Scholar 

  7. Brown SP, Safo PK, Regehr WG. Endocannabinoids inhibit transmission at granule cell to Purkinje cell synapses by modulating three types of presynaptic calcium channels. J Neurosci. 2004;24:5623–31.

    PubMed  Article  CAS  Google Scholar 

  8. Diana MA, 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. 2002;22:200–8.

    PubMed  CAS  Google Scholar 

  9. Egertova M, Elphick MR. Localisation of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB. J Comp Neurol. 2000;422:159–71.

    PubMed  Article  CAS  Google Scholar 

  10. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991;11:563–83.

    PubMed  CAS  Google Scholar 

  11. Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. 1998;83:393–411.

    PubMed  Article  CAS  Google Scholar 

  12. Chevaleyre V, Takahashi KA, Castillo PE. Endocannabinoidmediated synaptic plasticity in the CNS. Annu Rev Neurosci. 2006;29:37–75.

    PubMed  Article  CAS  Google Scholar 

  13. Llano I, Leresche N, Marty A. Calcium entry increases the sensitivity of cerebellar Purkinje cells to applied GABA and decreases inhibitory synaptic currents. Neuron. 1991;6: 565–74.

    PubMed  Article  CAS  Google Scholar 

  14. Vincent P, Armstrong CM, Marty A. Inhibitory synaptic currents in rat cerebellar Purkinje cells: modulation by postsynaptic depolarization. J Physiol. 1992;456:453–71.

    PubMed  CAS  Google Scholar 

  15. Pitler TA, Alger BE. Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells. J Neurosci. 1992;12:4122–32.

    PubMed  CAS  Google Scholar 

  16. Ohno-Shosaku T, Maejima T, Kano M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron. 2001;29:729–38.

    PubMed  Article  CAS  Google Scholar 

  17. Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature. 2001;410(6828):588–92.

    PubMed  Article  CAS  Google Scholar 

  18. Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: Depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol. 2004;142:9–19.

    PubMed  Article  CAS  Google Scholar 

  19. Safo PK, Regehr WG. Endocannabinoids control the induction of cerebellar LTD. Neuron. 2005;48:647–59.

    PubMed  Article  CAS  Google Scholar 

  20. Eilers J, Augustine GJ, Konnerth A. Subthreshold synaptic Ca2+ signalling in fine dendrites and spines of cerebellar Purkinje neurons. Nature. 1995;373(6510):155–8.

    PubMed  Article  CAS  Google Scholar 

  21. Neale SA, Garthwaite J, Batchelor AM. mGlu1 receptors mediate a post-tetanic depression at parallel fibre-Purkinje cell synapses in rat cerebellum. Eur J Neurosci. 2001;14: 1313–9.

    PubMed  Article  CAS  Google Scholar 

  22. Galante M, Diana MA. Group I metabotropic glutamate receptors inhibit GABA release at interneuron-Purkinje cell synapses through endocannabinoid production. J Neurosci. 2004;24(20):4865–74.

    PubMed  Article  CAS  Google Scholar 

  23. Maejima T, Oka S, Hashimotodani Y, Ohno-Shosaku T, Aiba A, Wu D, et al. Synaptically driven endocannabinoid release requires Ca2+-assisted metabotropic glutamate receptor subtype1 to phospholipase Cbeta4 signaling cascade in the cerebellum. J Neurosci. 2005;25(29):6826–35.

    PubMed  Article  CAS  Google Scholar 

  24. Knopfel T, Grandes P. Metabotropic glutamate receptors in the cerebellum with a focus on their function in Purkinje cells. Cerebellum. 2002;1:19–26.

    PubMed  Article  CAS  Google Scholar 

  25. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003;83: 1017–66.

    PubMed  CAS  Google Scholar 

  26. Brown SP, Brenowitz SD, Regehr WG. Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids. Nat Neurosci. 2003;6: 1048–57.

    PubMed  Article  CAS  Google Scholar 

  27. Batchelor AM, Madge DJ, Garthwaite J. Synaptic activation of metabotropic glutamate receptors in the parallel fibrePurkinje cell pathway in rat cerebellar slices. Neuroscience. 1994;63:911–5.

    PubMed  Article  CAS  Google Scholar 

  28. Tempia F, Alojado ME, Strata P, Knopfel T. Characterization of the mGluR(1)-mediated electrical and calcium signaling in Purkinje cells of mouse cerebellar slices. J Neurophysiol. 2001;86:1389–97.

    PubMed  CAS  Google Scholar 

  29. Marcaggi P, Attwell D. Endocannabinoid signaling depends on the spatial pattern of synapse activation. Nat Neurosci. 2005;8:776–81.

    PubMed  Article  CAS  Google Scholar 

  30. Wadiche JI, Jahr CE. Patterned expression of Purkinje cell glutamate transporters controls synaptic plasticity. Nat Neurosci. 2005;8:1329–34.

    PubMed  Article  CAS  Google Scholar 

  31. Wang SS, Denk W, Hausser M. Coincidence detection in single dendritic spines mediated by calcium release. Nat Neurosci. 2000;3:1266–73.

    PubMed  Article  CAS  Google Scholar 

  32. Denk W, Sugimori M, Llinas R. Two types of calcium response limited to single spines in cerebellar purkinje cells. Proc Natl Acad Sci USA. 1995;92:8279–82.

    PubMed  Article  CAS  Google Scholar 

  33. Kreitzer AC, Carter AG, Regehr WG. Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron. 2002;34:787–96.

    PubMed  Article  CAS  Google Scholar 

  34. Brenowitz SD, Regehr WG. Associative short-term synaptic plasticity mediated by endocannabinoids. Neuron. 2005;45: 419–31.

    PubMed  Article  CAS  Google Scholar 

  35. Pertwee RG. The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. Aaps J. 2005;7:E625–54.

    Article  Google Scholar 

  36. Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature. 1997;388(6644):773–8.

    PubMed  Article  CAS  Google Scholar 

  37. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258 (5090):1946–9.

    PubMed  Article  CAS  Google Scholar 

  38. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873–84.

    PubMed  Article  CAS  Google Scholar 

  39. Ueda N, Okamoto Y, Morishita J. N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: a novel enzyme of the beta-lactamase fold family releasing anandamide and other N-acylethanolamines. Life Sci. 2005;77:1750–8.

    PubMed  Article  CAS  Google Scholar 

  40. McKinney MK, Cravatt BF. Structure and function of fatty acid amide hydrolase. Annu Rev Biochem. 2005;74:411–32.

    PubMed  Article  CAS  Google Scholar 

  41. Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F, et al. Segregation of two endocannabinoidhydrolyzing enzymes into preand postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004;20:441–58.

    PubMed  Article  CAS  Google Scholar 

  42. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA. 2002;99:10819–24.

    PubMed  Article  CAS  Google Scholar 

  43. Breivogel CS, Walker JM, Huang SM, Roy MB, Childers SR. Cannabinoid signaling in rat cerebellar granule cells: Gprotein activation, inhibition of glutamate release and endogenous cannabinoids. Neuropharmacology. 2004;47: 81–91.

    PubMed  Article  CAS  Google Scholar 

  44. Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA. 2001;98:9371–6.

    PubMed  Article  CAS  Google Scholar 

  45. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, et al. An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005;435(7045): 1108–12.

    PubMed  Article  CAS  Google Scholar 

  46. Brenowitz SD, Regehr WG. Calcium dependence of retrograde inhibition by endocannabinoids at synapses onto Purkinje cells. J Neurosci. 2003;23:6373–84.

    PubMed  CAS  Google Scholar 

  47. Diana MA, Marty A. Characterization of depolarizationinduced suppression of inhibition using paired interneuron Purkinje cell recordings. J Neurosci. 2003;23:5906–18.

    PubMed  CAS  Google Scholar 

  48. Chadderton P, Margrie TW, Hausser M. Integration of quanta in cerebellar granule cells during sensory processing. Nature. 2004;428(6985):856–60.

    PubMed  Article  CAS  Google Scholar 

  49. Kitazawa S, Kimura T, Yin PB. Cerebellar complex spikes encode both destinations and errors in arm movements. Nature. 1998;392(6675):494–7.

    PubMed  Article  CAS  Google Scholar 

  50. Schultz W, Dickinson A. Neuronal coding of prediction errors. Annu Rev Neurosci. 2000;23:473–500.

    PubMed  Article  CAS  Google Scholar 

  51. Schmidt H, Stiefel KM, Racay P, Schwaller B, Eilers J. Mutational analysis of dendritic Ca2+ kinetics in rodent Purkinje cells: role of parvalbumin and calbindin D28k. J Physiol. 2003;551(Pt 1):13–32.

    PubMed  Article  CAS  Google Scholar 

  52. Tank DW, Sugimori M, Connor JA, Llinas RR. Spatially resolved calcium dynamics of mammalian Purkinje cells in cerebellar slice. Science. 1988;242(4879):773–7.

    PubMed  Article  CAS  Google Scholar 

  53. Ito M. Cerebellar long-term depression: Characterization, signal transduction, and functional roles. Physiol Rev. 2001;81:1143–95.

    PubMed  CAS  Google Scholar 

  54. Levenes C, Daniel H, Soubrie P, Crepel F. Cannabinoids decrease excitatory synaptic transmission and impair longterm depression in rat cerebellar Purkinje cells. J Physiol. 1998;510(Pt 3):867–79.

    PubMed  Article  CAS  Google Scholar 

  55. Daniel H, Levenes C, Crepel F. Cellular mechanisms of cerebellar LTD. Trends Neurosci. 1998;21:401–7.

    PubMed  Article  CAS  Google Scholar 

  56. Sakurai M. Calcium is an intracellular mediator of the climbing fiber in induction of cerebellar long-term depression. Proc Natl Acad Sci USA. 1990;87:3383–5.

    PubMed  Article  CAS  Google Scholar 

  57. Ito M. Long-term depression. Annu Rev Neurosci. 1989; 12:85–102.

    PubMed  Article  CAS  Google Scholar 

  58. Kano M, Kato M. Quisqualate receptors are specifically involved in cerebellar synaptic plasticity. Nature. 1987;325 (6101):276–9.

    PubMed  Article  CAS  Google Scholar 

  59. Ekerot CF, Kano M. Long-term depression of parallel fibre synapses following stimulation of climbing fibres. Brain Res. 1985;342:357–60.

    PubMed  Article  CAS  Google Scholar 

  60. Wang SS, Khiroug L, Augustine GJ. Quantification of spread of cerebellar long-term depression with chemical two-photon uncaging of glutamate. Proc Natl Acad Sci USA. 2000;97: 8635–40.

    PubMed  Article  CAS  Google Scholar 

  61. Reynolds T, Hartell NA. An evaluation of the synapse specificity of long-term depression induced in rat cerebellar slices. J Physiol. 2000;527 Pt 3:563–77.

    PubMed  Article  CAS  Google Scholar 

  62. Hartell NA. Strong activation of parallel fibers produces localized calcium transients and a form of LTD that spreads to distant synapses. Neuron. 1996;16:601–10.

    PubMed  Article  CAS  Google Scholar 

  63. Gerdeman GL, Ronesi J, Lovinger DM. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci. 2002;5:446–51.

    PubMed  CAS  Google Scholar 

  64. Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA. 2002;99:8384–8.

    PubMed  Article  CAS  Google Scholar 

  65. Sjostrom PJ, Turrigiano GG, Nelson SB. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron. 2003;39:641–54.

    PubMed  Article  Google Scholar 

  66. Chevaleyre V, Castillo PE. Heterosynaptic LTD of hippocampal GABAergic synapses: A novel role of endocannabinoids in regulating excitability. Neuron. 2003;38:461–72.

    PubMed  Article  CAS  Google Scholar 

  67. Kreitzer AC, Malenka RC. Dopamine modulation of statedependent endocannabinoid release and long-term depression in the striatum. J Neurosci. 2005;25:10537–45.

    PubMed  Article  CAS  Google Scholar 

  68. Shibuki K, Okada D. Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature. 1991;349(6307):326–8.

    PubMed  Article  CAS  Google Scholar 

  69. Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K, et al. Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell. 1994;79:377–88.

    PubMed  Article  CAS  Google Scholar 

  70. Lev-Ram V, Jiang T, Wood J, Lawrence DS, Tsien RY. Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. Neuron. 1997;18:1025–38.

    PubMed  Article  CAS  Google Scholar 

  71. Stefano GB, Esch T, Cadet P, Zhu W, Mantione K, Benson H. Endocannabinoids as autoregulatory signaling molecules: Coupling to nitric oxide and a possible association with the relaxation response. Med Sci Monit. 2003;9: RA63–75.

    Google Scholar 

  72. Deutsch DG, Goligorsky MS, Schmid PC, Krebsbach RJ, Schmid HH, Das SK, et al. Production and physiological actions of anandamide in the vasculature of the rat kidney. J Clin Invest. 1997;100:1538–46.

    PubMed  Article  CAS  Google Scholar 

  73. Hillard CJ, Muthian S, Kearn CS. Effects of CB (1) cannabinoid receptor activation on cerebellar granule cell nitric oxide synthase activity. FEBS Lett. 1999;459: 277–81.

    PubMed  Article  CAS  Google Scholar 

  74. Shin JH, Linden DJ. An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. J Neurophysiol. 2005;94:4281–9.

    PubMed  Article  CAS  Google Scholar 

  75. Kreitzer AC, Regehr WG. Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J Neurosci. 2001;21:RC174.

    PubMed  CAS  Google Scholar 

  76. Takahashi KA, Linden DJ. Cannabinoid receptor modulation of synapses received by cerebellar Purkinje cells. J Neurophysiol. 2000;83:1167–80.

    PubMed  CAS  Google Scholar 

  77. Yamasaki M, Hashimoto K, Kano M. Miniature synaptic events elicited by presynaptic Ca2+ rise are selectively suppressed by cannabinoid receptor activation in cerebellar Purkinje cells. J Neurosci. 2006;26:86–95.

    PubMed  Article  CAS  Google Scholar 

  78. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA. 1999;96:5780–5.

    PubMed  Article  CAS  Google Scholar 

  79. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science., 1999;283(5400):401–4.

    PubMed  Article  CAS  Google Scholar 

  80. Kawato M, Gomi H. The cerebellum and VOR/OKR learning models. Trends Neurosci. 1992;15:445–53.

    PubMed  Article  CAS  Google Scholar 

  81. Ito M. The cerebellum and neural control. New York: Raven Press; 1984.

    Google Scholar 

  82. Nakamura M, Sato K, Fukaya M, Araishi K, Aiba A, Kano M, et al. Signaling complex formation of phospholipase Cbeta4 with metabotropic glutamate receptor type 1alpha and 1,4,5trisphosphate receptor at the perisynapse and endoplasmic reticulum in the mouse brain. Eur J Neurosci. 2004;20: 2929–44.

    PubMed  Article  Google Scholar 

  83. Miyata M, Kim HT, Hashimoto K, Lee TK, Cho SY, Jiang H, et al. Deficient long-term synaptic depression in the rostral cerebellum correlated with impaired motor learning in phospholipase C beta4 mutant mice. Eur J Neurosci. 2001;13:1945–54.

    PubMed  Article  CAS  Google Scholar 

  84. Turrigiano GG, Nelson SB. Hebb and homeostasis in neuronal plasticity. Curr Opin Neurobiol. 2000;10:358–64.

    PubMed  Article  CAS  Google Scholar 

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  1. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA

    Patrick K. Safo, Benjamin F. Cravatt & Wade G. Regehr PhD

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  1. Patrick K. Safo
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  2. Benjamin F. Cravatt
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  3. Wade G. Regehr PhD
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Correspondence to Wade G. Regehr PhD.

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Safo, P.K., Cravatt, B.F. & Regehr, W.G. Retrograde endocannabinoid signaling in the cerebellar cortex. Cerebellum 5, 134–145 (2006). https://doi.org/10.1080/14734220600791477

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Key words

  • Cerebellar cortex
  • endocannabinoid signalling
  • parallel fibers