Abstract
Synaptic plasticity at the parallel fiber to Purkinje cell synapse has long been considered a cellular correlate for cerebellar motor learning. Functionally, long-term depression and long-term potentiation at these synapses seem to be the reverse of each other, with both pre- and post-synaptic expression occurring in both. However, different cerebellar motor learning paradigms have been shown to be asymmetric and not equally reversible. Here, we discuss the asymmetric reversibility shown in the vestibulo-ocular reflex and eyeblink conditioning and suggest that different cellular plasticity mechanisms might be recruited under different conditions leading to unequal reversibility.
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References
Marr D. A theory of cerebellar cortex. J Physiol. 1969;202:437–70.
Albus JS. A theory of cerebellar function. Math Biosci. 1971;10:25–61.
Ito M. Cerebellar control of the vestibulo-ocular reflex—around the flocculus hypothesis. Annu Rev Neurosci. 1982;5:275–96.
Ito M, Kawai N, Udo M, Sato N. Cerebellar-evoked disinhibition in dorsal Deiters neurones. Exp Brain Res. 1968;6:247–64.
De Zeeuw CI, Hansel C, Bian F, Koekkoek SKE, 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.
Hansel C, De Jeu M, Belmeguenai A, Houtman SH, Buitendijk GHS, Andreev D, et al. alphaCaMKII is essential for cerebellar LTD and motor learning. Neuron. 2006;51:835–43.
Titley HK, Heskin-Sweezie R, Broussard DM. The bidirectionality of motor learning in the vestibulo-ocular reflex is a function of cerebellar mGluR1 receptors. J Neurophysiol. 2010;104:3657–66.
Schonewille M, Gao Z, Boele H-JJ, et al. Reevaluating the role of LTD in cerebellar motor learning. Neuron. 2011;70:43–50.
Boyden ES, Raymond JL. Active reversal of motor memories reveals rules governing memory encoding. Neuron. 2003;39:1031–42.
Boyden ES, Katoh A, Raymond JL. Cerebellum-dependent learning: the role of multiple plasticity mechanisms. Annu Rev Neurosci. 2004;27:581–609.
Jörntell H, Hansel C. Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses. Neuron. 2006;52:227–38.
Andreescu CE, Milojkovic BA, Haasdijk ED, Kramer P, De Jong FH, Krust A, et al. Estradiol improves cerebellar memory formation by activating estrogen receptor beta. J Neurosci. 2007;27:10832–9.
Coesmans M, Weber JT, De Zeeuw CI, Hansel C. Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron. 2004;44:691–700.
Lev-Ram V, Mehta SB, Kleinfeld D, Tsien RY. Reversing cerebellar long-term depression. PNAS. 2003;100:15989–93.
Piochon C, Kloth AD, Grasselli G, et al. Cerebellar plasticity and motor learning deficits in a copy number variation mouse model of autism. Nat Commun. 2014;5:5586.
Broussard DM, Kassardjian CD. Learning in a simple motor system. Learn Mem. 2004;11:127–36.
Broussard DM, Titley HK, Antflick J, Hampson DR. Motor learning in the VOR: the cerebellar component. Exp Brain Res. 2011;210:451–63.
Robinson DA. Adaptive gain control of vestibuloocular reflex by the cerebellum. J Neurophysiol. 1976;39:954–69.
Lisberger SG, Miles FA, Optican LM. Frequency-selective adaptation: evidence for channels in the vestibulo-ocular reflex? J Neurosci. 1983;3:1234–44.
Raymond JL, Lisberger SG. Behavioural analysis of signals that guide learned changes in the amplitude and dynamics of the vestibulo-ocular reflex. J Neurosci. 1996;16:7791–802.
Kimpo RR, Boyden ES, Katoh A, Ke MC, Raymond JL. Distinct patterns of stimulus generalizations of increases and decreases in VOR gain. J Neurophysiol. 2005;94:3092–100.
Titley HK, Heskin-Sweezie R, Broussard DM. Consolidation and disruption of motor memory generalize across stimulus conditions in the vestibulo-ocular reflex. Brain Res. 2009;1267:37–43.
Miles FA, Eighmy BB. Long-term adaptive changes in primate vestibuloocular reflex. I. Behavioral observations. J Neurophysiol. 1980;43:1406–25.
Freeman JH, Steinmetz AB. Neural circuitry and plasticity mechanisms underlying delay eyeblink conditioning. Learn Mem. 2011;18:666–77.
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.
Kim JJ, Thompson RF. Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning. Trends Neurosci. 1997;20:177–81.
Perrett SP, Mauk MD. Extinction of conditioned eyelid responses requires the anterior lobe of cerebellar cortex. J Neurosci. 1995;15:2074–80.
Medina JF, Garcia KS, Mauk MD. A mechanism for savings in the cerebellum. J Neurosci. 2001;21:4081–9.
Wetmore DZ, Jirenhed D-A, Rasmussen A, Johansson F, Schnitzer MJ, Hesslow G. Bidirectional plasticity of Purkinje cells matches temporal features of learning. J Neurosci. 2014;34:1731–7.
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.
Piochon C, Kruskal P, Maclean J, Hansel C. Non-Hebbian spike-timing-dependent plasticity in cerebellar circuits. Front Neural Circuits. 2013;6:124
Thompson RF, Krupa DJ. Organization of memory traces in the mammalian brain. Annu Rev Neurosci. 1994;17:519–49.
Raymond JL, Lisberger SG. Neural learning rules for the vestibulo-ocular reflex. J Neurosci. 1998;18:9112–29.
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.
Kase M, Miller DC, Noda H. Discharges of Purkinje cells and mossy fibres in the cerebellar vermis of the monkey during saccadic eye movements and fixation. J Physiol. 1980;300:539–55.
Pellerin JP, Lamarre Y. Local field potential oscillations in primate cerebellar cortex during voluntary movement. J Neurophysiol. 1997;78:3502–7.
Wang SS, Denk W, Häusser M. Coincidence detection in single dendritic spines mediated by calcium release. Nat Neurosci. 2000;3:1266–73.
Finch EA, Augustine GJ. Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites. Nature. 1998;396:753–6.
Linden DJ, Connor JA. Participation of postsynaptic PKC in cerebellar long-term depression in culture. Science. 1991;254:1656–9.
Wang YT, Linden DJ. Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron. 2000;25:635–47.
Chung HJ, Steinberg JP, Huganir RL, Linden DJ. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science. 2003;300:1751–5.
Kawaguchi S, Hirano T. Gating of long-term depression by Ca2+/calmodulin-dependent protein kinase II through enhanced cGMP signalling in cerebellar Purkinje cells. J Physiol. 2013;591:1707–30.
Grasselli G, Hansel C. Cerebellar long-term potentiation: cellular mechanisms and role in learning. Int Rev Neurobiol. 2014;117:39–51.
Belmeguenai A, Hansel C. A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation. J Neurosci. 2005;25:10768–72.
Belmeguenai A, Botta P, Weber JT, Carta M, De Ruiter M, De Zeeuw CI, et al. Alcohol impairs long-term depression at the cerebellar parallel fiber-Purkinje cell synapse. J Neurophysiol. 2008;100:3167–74.
He Q, Titley H, Grasselli G, Piochon C, Hansel C. Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD. J Neurophysiol. 2013;109:1333–42.
Lev-Ram V, Wong ST, Storm DR, Tsien RY. A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP. PNAS. 2002;99:8389–93.
Wang D-J, Su L-D, Wang Y-N, Yang D, Sun C-L, Zhou L, et al. Long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses requires presynaptic and postsynaptic signaling cascades. J Neurosci. 2014;34:2355–64.
Huang Y, Man H-Y, Sekine-Aizawa Y, Han Y, Juluri K, Luo H, et al. S-nitrosylation of N-ethylmaleimide sensitive factor mediates surface expression of AMPA receptors. Neuron. 2005;46:533–40.
Kakegawa W, Yuzaki M. A mechanism underlying AMPA receptor trafficking during cerebellar long-term potentiation. PNAS. 2005;102:17846–51.
Hansel C. When the B-team runs plasticity: GluR2 receptor trafficking in cerebellar long-term potentiation. PNAS. 2005;102:18245–6.
Salin PA, Malenka RC, Nicoll RA. Cyclic AMP mediates a presynaptic form of LTP at cerebellar parallel fiber synapses. Neuron. 1996;16:797–803.
Qiu D, Knöpfel T. Presynaptically expressed long-term depression at cerebellar parallel fiber synapses. Eur J Physiol. 2009;457:865–75.
Chu C-P, Zhao G-Y, Jin R, Zhao S-N, Sun L, Qiu D-L. Properties of 4 Hz stimulation-induced parallel fiber-Purkinje cell presynaptic long-term plasticity in mouse cerebellar cortex in vivo. Eur J Neurosci. 2014;39:1624–31.
Ohyama T, Voicu H, Kalmbach B, Mauk MD. A decrementing form of plasticity apparent in cerebellar learning. J Neurosci. 2010;30:16993–7003.
van Beugen BJ, Nagaraja RY, Hansel C. Climbing fiber-evoked endocannabinoid signaling heterosynaptically suppresses presynaptic cerebellar long-term potentiation. J Neurosci. 2006;26:8289–94.
Rinaldo L, Hansel C. Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses via cannabinoid signaling. PNAS. 2013;110:11181–6.
Belmeguenai A, Hosy E, Bengtsson F, et al. Intrinsic plasticity complements long-term potentiation in parallel fiber input gain control in cerebellar Purkinje cells. J Neurosci. 2010;30:13630–43.
Hansel C, Linden DJ, D’Angelo E. Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum. Nat Neurosci. 2001;4:467–75.
Gao Z, van Beugen BJ, De Zeeuw CI. Distributed synergistic plasticity and cerebellar learning. Nat Rev Neurosci. 2012;13:619–35.
Ohyama T, Nores WL, Medina JF, Riusech FA, Mauk MD. Learning-induced plasticity in deep cerebellar nucleus. J Neurosci. 2006;26:12656–63.
Schonewille M, Belmeguenai A, Koekkoek SKE, et al. Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron. 2010;67:618–28.
Ly R, Bouvier G, Schonewille M, Arabo A, Rondi-Reig L, Léna C, et al. T-type channel blockade impairs long-term potentiation at the parallel fiber-Purkinje cell synapse and cerebellar learning. PNAS. 2013;110:20302–7.
Ke MC, Guo CC, Raymond JL. Elimination of climbing fiber instructive signals during motor learning. Nat Neurosci. 2009;12:1171–9.
Nguyen-Vu TDB, Kimpo RR, Rinaldi JM, Kohli A, Zeng H, Deisseroth K, et al. Cerebellar Purkinje cell activity drives motor learning. Nat Neurosci. 2013;16:1734–6.
Clopath C, Badura A, De Zeeuw CI, Brunel N. A cerebellar learning model of vestibulo-ocular reflex adaptation in wild-type and mutant mice. J Neurosci. 2014;34:7203–15.
Hansel C, Linden DJ. Long-term depression of the cerebellar climbing fiber-Purkinje neuron synapse. Neuron. 2000;26:473–82.
D’Angelo E, Rossi P, Armano S, Taglietti V. Evidence for NMDA and mGlu receptor-dependent long-term potentiation of mossy fiber-granule cell transmission in rat cerebellum. J Neurophysiol. 1999;81:277–87.
Armano S, Rossi P, Taglietti V, D’Angelo E. Long-term potentiation of intrinsic excitability at the mossy fiber-granule cell synapse of rat cerebellum. J Neurosci. 2000;20:5208–16.
Gall D, Prestori F, Sola E, D’Errico A, Roussel C, Forti L, et al. Intracellular calcium regulation by burst discharge determines bidirectional long-term synaptic plasticity at the cerebellum input stage. J Neurosci. 2005;25:4813–22.
Kano M, Rexhausen U, Dreessen J, Konnerth A. Synaptic excitation produces a long-lasting rebound potentiation of inhibitory synaptic signals in cerebellar Purkinje cells. Nature. 1992;356:601–4.
Duguid IC, Smart TG. Retrograde activation of presynaptic NMDA receptors enhances GABA release at cerebellar interneuron-Purkinje cell synapses. Nat Neurosci. 2004;7:525–33.
Aizenman CD, Manis PB, Linden DJ. Polarity of long-term synaptic gain change is related to postsynaptic spike firing at a cerebellar inhibitory synapse. Neuron. 1998;21:827–35.
Pugh JR, Raman IM. Potentiation of mossy fiber EPSCs in the cerebellar nuclei by NMDA receptor activation followed by postinhibitory rebound current. Neuron. 2006;51:113–23.
du Lac S, Raymond JL, Sejnowski TJ, Lisberger SG. Learning and memory in the vestibulo-ocular reflex. Annu Rev Neurosci. 1995;18:409–41.
Prestori F, Bonardi C, Mapelli L, et al. Gating of long-term potentiation by nicotinic acetylcholine receptors at the cerebellum input stage. PLoS ONE. 2013;8:e64828.
Boele H-J, Koekkoek SKE, De Zeeuw CI, Ruigrok TJH. Axonal sprouting and formation of terminals in the adult cerebellum during associative motor learning. J Neurosci. 2013;33:17897–907.
Wulff P, Schonewille M, Renzi M, et al. Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning. Nat Neurosci. 2009;12:1042–9.
Andreescu CE, Prestori F, Brandalise F, et al. NR2A subunit of the N-methyl D-aspartate receptors are required for potentiation at the mossy fiber to granule cell synapse and vestibulo-cerebellar motor learning. Neuroscience. 2011;176:274–83.
Yang Y, Lisberger SG. Role of plasticity at different sites across the time course of cerebellar motor learning. J Neurosci. 2014;34:7077–90.
Titley HK, Heskin-Sweezie R, Chung JJ, Kassardjian CD, Razik F, Broussard DM. Rapid consolidation of motor memory in the vestibuloocular reflex. J Neurophysiol. 2007;98:3809–12.
Kassardjian CD, Tan Y-F, Chung J-YJ, Heskin R, Peterson MJ, Broussard DM. The site of a motor memory shifts with consolidation. J Neurosci. 2005;25:7979–85.
Shutoh F, Ohki M, Kitazawa H, Itohara S, Nagao S. Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation. Neuroscience. 2006;139:767–77.
Acknowledgements
The authors thank D. Broussard and members of the Hansel lab for their many helpful discussions. This work was supported by the National Institute of Neurological Disorders and Stroke (NS062771 to C.H.).
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The authors declare no conflict of interest.
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Titley, H.K., Hansel, C. Asymmetries in Cerebellar Plasticity and Motor Learning. Cerebellum 15, 87–92 (2016). https://doi.org/10.1007/s12311-014-0635-7
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DOI: https://doi.org/10.1007/s12311-014-0635-7