The Cerebellum

, Volume 11, Issue 3, pp 706–717 | Cite as

Calcium as a Trigger for Cerebellar Long-Term Synaptic Depression

  • Elizabeth A. Finch
  • Keiko Tanaka
  • George J. AugustineEmail author
Review Article


Cerebellar long-term depression (LTD) is a form of long-term synaptic plasticity that is triggered by calcium (Ca2+) signals in the postsynaptic Purkinje cell. This Ca2+ comes both from IP3-mediated release from intracellular Ca2+ stores, as well as from Ca2+ influx through voltage-gated Ca2+ channels. The Ca2+ signal that triggers LTD occurs locally within dendritic spines and is due to supralinear summation of signals coming from these two Ca2+ sources. The properties of this postsynaptic Ca2+ signal can explain several features of LTD, such as its associativity, synapse specificity, and dependence on the timing of synaptic activity, and can account for the slow kinetics of LTD expression. Thus, from a Ca2+ signaling perspective, LTD is one of the best understood forms of synaptic plasticity.


Synaptic plasticity Purkinje cell IP3 Ca2+ channel Protein kinase C 



This work was supported by the World Class Institute (WCI) Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, Technology of Korea (MEST) with NRF Grant Number: WCI 2009-003, and NIH grant RO1-MH06605 for E.A.F. respectively.

Conflict of Interest Notification

None of the authors of this review article have a financial interest related to this work.


  1. 1.
    Ito M, Kano M. Long-lasting depression of parallel fiber–Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex. Neurosci Lett. 1982;33:253–8.PubMedGoogle Scholar
  2. 2.
    Ito M, Sakurai M, Tongroach P. Climbing fibre induced depression of both mossy fibre responsiveness and glutamate sensitivity of cerebellar Purkinje cells. J Physiol. 1982;324:113–34.PubMedGoogle Scholar
  3. 3.
    Ekerot CF, Kano M. Long-term depression of parallel fibre synapses following stimulation of climbing fibres. Brain Res. 1985;342:357–60.PubMedGoogle Scholar
  4. 4.
    Sakurai M. Synaptic modification of parallel fibre-Purkinje cell transmission in in vitro guinea-pig cerebellar slices. J Physiol. 1987;394:463–80.PubMedGoogle Scholar
  5. 5.
    Konnerth A, Dreessen J, Augustine GJ. Brief dendritic calcium signals initiate long-lasting synaptic depression in cerebellar Purkinje cells. Proc Natl Acad Sci USA. 1992;89:7051–5.PubMedGoogle Scholar
  6. 6.
    Chen C, Thompson RF. Temporal specificity of long-term depression in parallel fiber–Purkinje synapses in rat cerebellar slice. Learn Mem. 1995;2:185–98.PubMedGoogle Scholar
  7. 7.
    Matsuda S, Launey T, Mikawa S, Hirai H. Disruption of AMPA receptor GluR2 clusters following long-term depression induction in cerebellar Purkinje neurons. EMBO J. 2000;19:2765–74.PubMedGoogle Scholar
  8. 8.
    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.PubMedGoogle Scholar
  9. 9.
    Wang YT, Linden DJ. Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron. 2000;25:635–47.PubMedGoogle Scholar
  10. 10.
    Xia J, Chung HJ, Wihler C, Huganir RL, Linden DJ. Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron. 2000;28:499–510.PubMedGoogle Scholar
  11. 11.
    Weber JT, De Zeeuw CI, Linden DJ, Hansel C. Long-term depression of climbing fiber-evoked calcium transients in Purkinje cell dendrites. Proc Natl Acad Sci USA. 2003;100:2878–83.PubMedGoogle Scholar
  12. 12.
    Thompson RF. Neural mechanisms of classical conditioning in mammals. Phil Trans R Soc Lond. 1990;329:161–70.Google Scholar
  13. 13.
    Lisberger S, Cerebellar LTD. A molecular mechanism of behavioral learning? Cell. 1998;92:701–4.PubMedGoogle Scholar
  14. 14.
    Mauk MD, Garcia KS, Medina JF, Steele PM. Does cerebellar LTD mediate motor learning? Toward a resolution without a smoking gun. Neuron. 1998;20:359–62.PubMedGoogle Scholar
  15. 15.
    Ito M. Mechanisms of motor learning in the cerebellum. Brain Res. 2000;886:237–45.PubMedGoogle Scholar
  16. 16.
    Koekkoek SK, Hulscher HC, Dortland BR, Hensbroek RA, Elgersma Y, Ruigrok TJ, et al. Cerebellar LTD and learning-dependent timing of conditioned eyelid responses. Science. 2003;301:1736–9.PubMedGoogle Scholar
  17. 17.
    Burguière E, Arleo A, Hojjati M, Elgersma Y, De Zeeuw CI, Berthoz A, et al. Spatial navigation impairment in mice lacking cerebellar LTD: a motor adaptation deficit? Nat Neurosci. 2005;8:1292–4.PubMedGoogle Scholar
  18. 18.
    Kasumu A, Bezprozvanny I. Deranged calcium signaling in Purkinje cells and pathogenesis in spinocerebellar ataxia 2 (SCA2) and other ataxias. Cerebellum. 2011. doi: 10.1007/s12311-010-0182-9.
  19. 19.
    Schonewille M, Gao Z, Boele HJ, Veloz MF, Amerika WE, Simek AA, et al. Reevaluating the role of LTD in cerebellar motor learning. Neuron. 2011;70:43–50.PubMedGoogle Scholar
  20. 20.
    Eilers J, Takechi H, Finch EA, Augustine GJ, Konnerth A. Local dendritic Ca2+ signaling induces cerebellar long-term depression. Learn Mem. 1997;4:159–68.PubMedGoogle Scholar
  21. 21.
    Wang SS, Denk W, Hausser M. Coincidence detection in single dendritic spines mediated by calcium release. Nat Neurosci. 2000;3:1266–73.PubMedGoogle Scholar
  22. 22.
    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.PubMedGoogle Scholar
  23. 23.
    Shibuki K, Okada D. Cerebellar long-term potentiation under suppressed postsynaptic Ca2+ activity. Neuroreport. 1992;3:231–4.PubMedGoogle Scholar
  24. 24.
    Finch EA, Augustine GJ. Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites. Nature. 1998;396:753–6.PubMedGoogle Scholar
  25. 25.
    Miyata M, Finch EA, Khiroug L, Hashimoto K, Hayasaka S, Oda SI, et al. Local calcium release in dendritic spines required for long-term synaptic depression. Neuron. 2000;28:233–44.PubMedGoogle Scholar
  26. 26.
    Tanaka K, Khiroug L, Santamaria F, Doi T, Ogasawara H, Ellis-Davies GC, et al. Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator. Neuron. 2007;54:787–800.PubMedGoogle Scholar
  27. 27.
    Crépel F, Jaillard D. Pairing of pre- and postsynaptic activities in cerebellar Purkinje cells induces long-term changes in synaptic efficacy in vitro. J Physiol. 1991;432:123–41.PubMedGoogle Scholar
  28. 28.
    Linden DJ, Dickinson MH, Smeyne M, Connor JA. A long-term depression of AMPA currents in cultured cerebellar Purkinje neurons. Neuron. 1991;7:81–9.PubMedGoogle Scholar
  29. 29.
    Kasono K, Hirano T. Critical role of postsynaptic calcium in cerebellar long-term depression. Neuroreport. 1994;6:17–20.PubMedGoogle Scholar
  30. 30.
    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.PubMedGoogle Scholar
  31. 31.
    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.PubMedGoogle Scholar
  32. 32.
    Konnerth A, Llano I, Armstrong CM. Synaptic currents in cerebellar Purkinje cells. Proc Natl Acad Sci USA. 1990;87:2662–5.PubMedGoogle Scholar
  33. 33.
    Perkel DJ, Hestrin S, Sah P, Nicoll RA. Excitatory synaptic currents in Purkinje cells. Proc Biol Sci. 1990;241:116–21.PubMedGoogle Scholar
  34. 34.
    Llano I, Marty A, Armstrong CM, Konnerth A. Synaptic- and agonist-induced excitatory currents of Purkinje cells in rat cerebellar slices. J Physiol. 1991;434:183–213.PubMedGoogle Scholar
  35. 35.
    Eccles JC, Llinas R, Sasaki K. The action of antidromic impulses on the cerebellar Purkinje cells. J Physiol. 1966;182:316–45.PubMedGoogle Scholar
  36. 36.
    Llinas R, Sugimori M. Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. J Physiol. 1980;305:171–95.PubMedGoogle Scholar
  37. 37.
    Carta M, Mameli M, Valenzuela CF. Alcohol potently modulates climbing fiber–>Purkinje neuron synapses: role of metabotropic glutamate receptors. J Neurosci. 2006;26:1906–12.PubMedGoogle Scholar
  38. 38.
    Cavelier P, Lohof AM, Lonchamp E, Beekenkamp H, Mariani J, Bossu JL. Participation of low-threshold Ca2+ spike in the Purkinje cells complex spike. Neuroreport. 2008;19:299–303.PubMedGoogle Scholar
  39. 39.
    Hurlock EC, McMahon A, Joho RH. Purkinje-cell-restricted restoration of Kv3.3 function restores complex spikes and rescues motor coordination in Kcnc3 mutants. J Neurosci. 2008;28:4640–8.PubMedGoogle Scholar
  40. 40.
    Zagha E, Lang EJ, Rudy B. Kv3.3 channels at the Purkinje cell soma are necessary for generation of the classical complex spike waveform. J Neurosci. 2008;28:1291–300.PubMedGoogle Scholar
  41. 41.
    Ross WN, Werman R. Mapping calcium transients in the dendrites of Purkinje cells from the guinea-pig cerebellum in vitro. J Physiol. 1987;389:319–36.PubMedGoogle Scholar
  42. 42.
    Miyakawa H, Lev-Ram V, Lasser-Ross N, Ross WN. Calcium transients evoked by climbing fiber and parallel fiber synaptic inputs in guinea pig cerebellar Purkinje neurons. J Neurophysiol. 1992;68:1178–89.PubMedGoogle Scholar
  43. 43.
    Nusser Z, Mulvihill E, Streit P, Somogyi P. Subsynaptic segregation of metabotropic and ionotropic glutamate receptors as revealed by immunogold localization. Neuroscience. 1994;61:421–7.PubMedGoogle Scholar
  44. 44.
    Petralia RS, Zhao HM, Wang YX, Wenthold RJ. Variations in the tangential distribution of postsynaptic glutamate receptors in Purkinje cell parallel and climbing fiber synapses during development. Neuropharmacology. 1998;37:1321–34.PubMedGoogle Scholar
  45. 45.
    Dzubay JA, Otis TS. Climbing fiber activation of metabotropic glutamate receptors on cerebellar purkinje neurons. Neuron. 2002;36:1159–67.PubMedGoogle Scholar
  46. 46.
    Piochon C, Irinopoulou T, Brusciano D, Bailly Y, Mariani J, Levenes C. NMDA receptor contribution to the climbing fiber response in the adult mouse Purkinje cell. J Neurosci. 2007;27:10797–809.PubMedGoogle Scholar
  47. 47.
    Renzi M, Farrant M, Cull-Candy SG. Climbing-fibre activation of NMDA receptors in Purkinje cells of adult mice. J Physiol. 2007;585:91–101.PubMedGoogle Scholar
  48. 48.
    Piochon C, Levenes C, Ohtsuki G, Hansel C. Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum. J Neurosci. 2010;30:15330–5.PubMedGoogle Scholar
  49. 49.
    Momiyama A, Feldmeyer D, Cull-Candy SG. Identification of a native low-conductance NMDA channel with reduced sensitivity to Mg2+ in rat central neurones. J Physiol. 1996;494:479–92.PubMedGoogle Scholar
  50. 50.
    Eilers J, Augustine GJ, Konnerth A. Subthreshold synaptic Ca2+ signalling in fine dendrites and spines of cerebellar Purkinje neurons. Nature. 1995;373:155–8.PubMedGoogle Scholar
  51. 51.
    Eilers J, Plant T, Konnerth A. Localized calcium signalling and neuronal integration in cerebellar Purkinje neurones. Cell Calcium. 1996;20:215–26.PubMedGoogle Scholar
  52. 52.
    Takechi H, Eilers J, Konnerth A. A new class of synaptic response involving calcium release in dendritic spines. Nature. 1998;396:757–60.PubMedGoogle Scholar
  53. 53.
    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.PubMedGoogle Scholar
  54. 54.
    Conquet F, Bashir ZI, Davies CH, Daniel H, Ferraguti F, Bordi F, et al. Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1. Nature. 1994;372:237–43.PubMedGoogle Scholar
  55. 55.
    Ichise T, Kano M, Hashimoto K, Yanagihara D, Nakao K, Shigemoto R, et al. mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science. 2000;288:1832–5.PubMedGoogle Scholar
  56. 56.
    Batchelor AM, Madge DJ, Garthwaite J. Synaptic activation of metabotropic glutamate receptors in the parallel fibre-Purkinje cell pathway in rat cerebellar slices. Neuroscience. 1994;63:911–5.PubMedGoogle Scholar
  57. 57.
    Hirono M, Sugiyama T, Kishimoto Y, Sakai I, Miyazawa T, Kishio M, et al. Phospholipase Cb4 and protein kinase Ca and/or protein kinase CbI are involved in the induction of long term depression in cerebellar Purkinje cells. J Biol Chem. 2001;276:45236–42.PubMedGoogle Scholar
  58. 58.
    Mikoshiba K, Goto J. Inositol 1,4,5-trisphosphate receptor-mediated calcium release in Purkinje cells: From molecular mechanism to behaviour. Cerebellum. 2011. doi: 10.1007/s12311-011-0270-5.
  59. 59.
    Batchelor AM, Garthwaite J. Novel synaptic potentials in cerebellar Purkinje cells: probable mediation by metabotropic glutamate receptors. Neuropharmacology. 1993;32:11–20.PubMedGoogle Scholar
  60. 60.
    Hartmann J, Dragicevic E, Adelsberger H, Henning HA, Sumser M, Abramowitz J, et al. TRPC3 channels are required for synaptic transmission and motor coordination. Neuron. 2008;59:392–8.PubMedGoogle Scholar
  61. 61.
    Khodakhah K, Armstrong CM. Induction of long-term depression and rebound potentiation by inositol trisphosphate in cerebellar Purkinje neurons. Proc Natl Acad Sci USA. 1997;94:14009–14.PubMedGoogle Scholar
  62. 62.
    Inoue T, Kato K, Kohda K, Mikoshiba K. Type 1 inositol 1,4,5-trisphosphate receptor is required for induction of long-term depression in cerebellar Purkinje neurons. J Neurosci. 1998;18:5366–73.PubMedGoogle Scholar
  63. 63.
    Daniel H, Levenes C, Fagni L, Conquet F, Bockaert J, Crépel F. Inositol-1,4,5-trisphosphate-mediated rescue of cerebellar long-term depression in subtype 1 metabotropic glutamate receptor mutant mouse. Neuroscience. 1999;92:1–6.PubMedGoogle Scholar
  64. 64.
    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;551:13–32.PubMedGoogle Scholar
  65. 65.
    Sarkisov DV, Wang SS. Order-dependent coincidence detection in cerebellar Purkinje neurons at the inositol trisphosphate receptor. J Neurosci. 2008;28:133–42.PubMedGoogle Scholar
  66. 66.
    Brenowitz SD, Regehr WG. Associative short-term synaptic plasticity mediated by endocannabinoids. Neuron. 2005;45:419–31.PubMedGoogle Scholar
  67. 67.
    Yang SN, Tang YG, Zucker RS. Selective induction of LTP and LTD by postsynaptic [Ca2+]i elevation. J Neurophysiol. 1999;81:781–7.PubMedGoogle Scholar
  68. 68.
    Bienenstock EL, Cooper LN, Munro PW. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J Neurosci. 1982;2:32–48.PubMedGoogle Scholar
  69. 69.
    Jörntell H, Hansel C. Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber–Purkinje cell synapses. Neuron. 2006;52:227–38.PubMedGoogle Scholar
  70. 70.
    Berridge MJ. Cell signalling. A tale of two messengers. Nature. 1993;365:388–9.PubMedGoogle Scholar
  71. 71.
    Iino M. Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced Ca release in smooth muscle cells of the guinea pig taenia caeci. J Gen Physiol. 1990;95:1103–22.PubMedGoogle Scholar
  72. 72.
    Bezprozvanny I, Watras J, Ehrlich BE. Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature. 1991;351:751–4.PubMedGoogle Scholar
  73. 73.
    Finch EA, Turner TJ, Goldin SM. Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release. Science. 1991;252:443–6.PubMedGoogle Scholar
  74. 74.
    Linden DJ. Input-specific induction of cerebellar long-term depression does not require presynaptic alteration. Learn Mem. 1994;1:121–8.PubMedGoogle Scholar
  75. 75.
    Ogasawara H, Doi T, Doya K, Kawato M. Nitric oxide regulates input specificity of long-term depression and context dependence of cerebellar learning. PLoS Comput Biol. 2007;3:e179.PubMedGoogle Scholar
  76. 76.
    Reynolds T, Hartell NA. An evaluation of the synapse specificity of long-term depression induced in rat cerebellar slices. J Physiol. 2000;527:563–77.PubMedGoogle Scholar
  77. 77.
    Santamaria F, Wils S, De Schutter E, Augustine GJ. Anomalous diffusion in Purkinje cell dendrites caused by spines. Neuron. 2006;52:635–48.PubMedGoogle Scholar
  78. 78.
    Shibuki K, Okada D. Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature. 1991;349:326–8.PubMedGoogle Scholar
  79. 79.
    Lev-Ram V, Nebyelul Z, Ellisman MH, Huang PL, Tsien RY. Absence of cerebellar long-term depression in mice lacking neuronal nitric oxide synthase. Learn Mem. 1997;4:169–77.PubMedGoogle Scholar
  80. 80.
    Namiki S, Kakizawa S, Hirose K, Iino M. NO signalling decodes frequency of neuronal activity and generates synapse-specific plasticity in mouse cerebellum. J Physiol. 2005;566:849–63.PubMedGoogle Scholar
  81. 81.
    Crépel F, Jaillard D. Protein kinases, nitric oxide and long-term depression of synapses in the cerebellum. Neuroreport. 1990;1:133–6.PubMedGoogle Scholar
  82. 82.
    Ito M, Karachot L. Messengers mediating long-term desensitization in cerebellar Purkinje cells. Neuroreport. 1990;1:129–32.PubMedGoogle Scholar
  83. 83.
    Daniel H, Hemart N, Jaillard D, Crépel F. Long-term depression requires nitric oxide and guanosine 3′:5′ cyclic monophosphate production in rat cerebellar Purkinje cells. Eur J Neurosci. 1993;5:1079–82.PubMedGoogle Scholar
  84. 84.
    Lev-Ram V, Makings LR, Keitz PF, Kao JP, Tsien RY. Long-term depression in cerebellar Purkinje neurons results from coincidence of nitric oxide and depolarization-induced Ca2+ transients. Neuron. 1995;15:407–15.PubMedGoogle Scholar
  85. 85.
    Reynolds T, Hartell NA. Roles for nitric oxide and arachidonic acid in the induction of heterosynaptic cerebellar LTD. Neuroreport. 2001;12:133–6.PubMedGoogle Scholar
  86. 86.
    Tanaka K, Augustine GJ. Dual roles for nitric oxide in cerebellar long-term depression. Program no. 3365 2008 Abstract viewer and itinerary planner. Atlanta: Society for Neuroscience; 2008.Google Scholar
  87. 87.
    Safo P, Regehr WG. Timing dependence of the induction of cerebellar LTD. Neuropharmacology. 2008;54:213–8.PubMedGoogle Scholar
  88. 88.
    Okubo Y, Kakizawa S, Hirose K, Iino M. Cross talk between metabotropic and ionotropic glutamate receptor-mediated signaling in parallel fiber-induced inositol 1,4,5-trisphosphate production in cerebellar Purkinje cells. J Neurosci. 2004;24:9513–20.PubMedGoogle Scholar
  89. 89.
    Linden DJ. A protein synthesis-dependent late phase of cerebellar long-term depression. Neuron. 1996;17:483–90.PubMedGoogle Scholar
  90. 90.
    Levenes C, Daniel H, Crepel F. Long-term depression of synaptic transmission in the cerebellum: cellular and molecular mechanisms revisited. Prog Neurobiol. 1998;55:79–91.PubMedGoogle Scholar
  91. 91.
    Ito M. Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev. 2001;81:1143–95.PubMedGoogle Scholar
  92. 92.
    Linden DJ, Connor JA. Participation of postsynaptic PKC in cerebellar long-term depression in culture. Science. 1991;254:1656–9.PubMedGoogle Scholar
  93. 93.
    Hartell NA. cGMP acts within cerebellar Purkinje cells to produce long term depression via mechanisms involving PKC and PKG. Neuroreport. 1994;5:833–6.PubMedGoogle Scholar
  94. 94.
    De Zeeuw CI, Hansel C, Bian F, Koekkoek SK, van Alphen AM, Linden DJ, et al. Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron. 1998;20:495–508.PubMedGoogle Scholar
  95. 95.
    Goossens J, Daniel H, Rancillac A, van der Steen J, Oberdick J, Crépel F, et al. Expression of protein kinase C inhibitor blocks cerebellar long-term depression without affecting Purkinje cell excitability in alert mice. J Neurosci. 2001;21:5813–23.PubMedGoogle Scholar
  96. 96.
    Crépel F, Krupa M. Activation of protein kinase C induces a long-term depression of glutamate sensitivity of cerebellar Purkinje cells. An in vitro study. Brain Res. 1988;458:397–401.PubMedGoogle Scholar
  97. 97.
    Chung HJ, Steinberg JP, Huganir RL, Linden DJ. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science. 2003;300:1751–5.PubMedGoogle Scholar
  98. 98.
    Steinberg JP, Takamiya K, Shen Y, Xia J, Rubio ME, Yu S, et al. Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. Neuron. 2006;49:845–60.PubMedGoogle Scholar
  99. 99.
    Tanaka K, Augustine GJ. A positive feedback signal transduction loop determines timing of cerebellar long-term depression. Neuron. 2008;59:608–20.PubMedGoogle Scholar
  100. 100.
    Bhalla US, Iyengar R. Emergent properties of networks of biological signaling pathways. Science. 1999;283:381–7.PubMedGoogle Scholar
  101. 101.
    Kuroda S, Schweighofer N, Kawato M. Exploration of signal transduction pathways in cerebellar long-term depression by kinetic simulation. J Neurosci. 2001;21:5693–702.PubMedGoogle Scholar
  102. 102.
    Kawasaki H, Fujii H, Gotoh Y, Morooka T, Shimohama S, Nishida E, et al. Requirement for mitogen-activated protein kinase in cerebellar long term depression. J Biol Chem. 1999;274:13498–502.PubMedGoogle Scholar
  103. 103.
    Murashima M, Hirano T. Entire course and distinct phases of day-lasting depression of miniature EPSC amplitudes in cultured Purkinje neurons. J Neurosci. 1999;19:7326–33.PubMedGoogle Scholar
  104. 104.
    Le TD, Shirai Y, Okamoto T, Tatsukawa T, Nagao S, Shimizu T, et al. Lipid signaling in cytosolic phospholipase A2a-cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning. Proc Natl Acad Sci USA. 2010;107:3198–203.PubMedGoogle Scholar
  105. 105.
    Hansel C, de Jeu M, Belmeguenai A, Houtman SH, Buitendijk GH, Andreev D, et al. aCaMKII Is essential for cerebellar LTD and motor learning. Neuron. 2006;51:835–43.PubMedGoogle Scholar
  106. 106.
    van Woerden GM, Hoebeek FE, Gao Z, Nagaraja RY, Hoogenraad CC, Kushner SA, et al. bCaMKII controls the direction of plasticity at parallel fiber–Purkinje cell synapses. Nat Neurosci. 2009;12:823–5.PubMedGoogle Scholar
  107. 107.
    Correia SS, Bassani S, Brown TC, Lise MF, Backos DS, El-Husseini A, et al. Motor protein-dependent transport of AMPA receptors into spines during long-term potentiation. Nat Neurosci. 2008;11:457–66.PubMedGoogle Scholar
  108. 108.
    Safo PK, Regehr WG. Endocannabinoids control the induction of cerebellar LTD. Neuron. 2005;48:647–59.PubMedGoogle Scholar
  109. 109.
    Carey MR, Myoga MH, McDaniels KR, Marsicano G, Lutz B, Mackie K, et al. Presynaptic CB1 receptors regulate synaptic plasticity at cerebellar parallel fiber synapses. J Neurophysiol. 2011;105:958–63.PubMedGoogle Scholar
  110. 110.
    Cho RW, Park JM, Wolff SB, Xu D, Hopf C, Kim JA, et al. mGluR1/5-dependent long-term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE. Neuron. 2008;57:858–71.PubMedGoogle Scholar
  111. 111.
    Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, et al. D-serine regulates cerebellar LTD and motor coordination through the delta2 glutamate receptor. Nat Neurosci. 2011;14:603–11.PubMedGoogle Scholar
  112. 112.
    Karachot L, Shirai Y, Vigot R, Yamamori T, Ito M. Induction of long-term depression in cerebellar Purkinje cells requires a rapidly turned over protein. J Neurophysiol. 2001;86:280–9.PubMedGoogle Scholar
  113. 113.
    Ahn S, Ginty DD, Linden DJ. A late phase of cerebellar long-term depression requires activation of CaMKIV and CREB. Neuron. 1999;23:559–68.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Elizabeth A. Finch
    • 1
  • Keiko Tanaka
    • 2
  • George J. Augustine
    • 2
    Email author
  1. 1.Department of MedicineDuke University Medical CenterDurhamUSA
  2. 2.Center for Functional ConnectomicsKorea Institute of Science and TechnologySeoulRepublic of Korea

Personalised recommendations