Abstract
Formation of excess synaptic connections at perinatal stage and subsequent elimination of redundant synapses and strengthening of the surviving ones are crucial steps for functional neural circuit formation in developing nervous system. Shortly after birth, excitatory synapses are formed on the somata of Purkinje cells (PCs) from climbing fibers (CFs) that originate from neurons in the inferior olive of the contralateral medulla oblongata. At this developmental stage, each PC is innervated by multiple (around five) CFs with equal strengths. Subsequently, a single CF is selectively strengthened relative to other CFs during the first postnatal week. Then, around postnatal day 9 (P9), only the strongest CF (“winner” CF) starts to extend its innervation to PC dendrites. On the other hand, synapses of the weaker CFs (“loser” CFs) remain on the soma and the most proximal portion of the dendrite, and they are eliminated progressively during the second and the third postnatal weeks. From P6 to P11, the elimination proceeds independently of the formation of the synapses on PC dendrites from parallel fibers (PFs), the other excitatory inputs to PCs. From P12 and thereafter, the elimination of weaker CFs requires normal PF-PC synapse formation and is presumably dependent on the PF synaptic inputs that activate type 1 metabotropic glutamate receptor (mGluR1) and its downstream signaling in PCs. Most PCs become mono-innervated by single CFs in the third postnatal week. This chapter integrates the current knowledge of synaptogenesis and subsequent synapse elimination at CF to PC connections during postnatal cerebellar development.
References
Altman J, Bayer SA (1997) Development of the cerebellar system: in relation to its evolution, structure, and functions. CRC Press, Boca Raton
Andjus PR, Zhu L, Cesa R, Carulli D, Strata P (2003) A change in the pattern of activity affects the developmental regression of the Purkinje cell polyinnervation by climbing fibers in the rat cerebellum. Neuroscience 121:563–572
Armengol JA, Sotelo C (1991) Early dendritic development of Purkinje cells in the rat cerebellum. A light and electron microscopic study using axonal tracing in ‘in vitro’ slices. Brain Res Dev Brain Res 64:95–114
Batchelor AM, Madge DJ, Garthwaite J (1994) Synaptic activation of metabotropic glutamate receptors in the parallel fibre-Purkinje cell pathway in rat cerebellar slices. Neuroscience 63:911–915
Bishop DL, Misgeld T, Walsh MK, Gan WB, Lichtman JW (2004) Axon branch removal at developing synapses by axosome shedding. Neuron 44:651–661
Bosman LW, Hartmann J, Barski JJ, Lepier A, Noll-Hussong M, Reichardt LF, Konnerth A (2006) Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells. Brain Cell Biol 35:87–101
Bosman LW, Takechi H, Hartmann J, Eilers J, Konnerth A (2008) Homosynaptic long-term synaptic potentiation of the “winner” climbing fiber synapse in developing Purkinje cells. J Neurosci 28:798–807
Bravin M, Rossi F, Strata P (1995) Different climbing fibres innervate separate dendritic regions of the same Purkinje cell in hypogranular cerebellum. J Comp Neurol 357:395–407
Cajal SR (1911) Histologie du systeme nerveux de l'homme et des vertebres, vol II. Maloine, Paris
Cesa R, Scelfo B, Strata P (2007) Activity-dependent presynaptic and postsynaptic structural plasticity in the mature cerebellum. J Neurosci 27:4603–4611
Chedotal A, Sotelo C (1993) The ‘creeper stage’ in cerebellar climbing fiber synaptogenesis precedes the ‘pericellular nest’–ultrastructural evidence with parvalbumin immunocytochemistry. Brain Res Dev Brain Res 76:207–220
Clements JD (1996) Transmitter time course in the synaptic cleft: its role in central synaptic function. Trends Neurosci 19:163–171
Crepel F (1971) Maturation of climbing fiber responses in the rat. Brain Res 35:272–276
Crepel F (1982) Regression of functional synapses in the immature mammalian cerebellum. Trends Neurosci 5:266–269
Crepel F, Delhaye-Bouchaud N (1979) Distribution of climbing fibres on cerebellar Purkinje cells in X-irradiated rats. An electrophysiological study. J Physiol 290:97–112
Crepel F, Mariani J (1976) Multiple innervation of Purkinje cells by climbing fibers in the cerebellum of the weaver mutant mouse. J Neurobiol 7:579–582
Crepel F, Mariani J, Delhaye-Bouchaud N (1976) Evidence for a multiple innervation of Purkinje cells by climbing fibers in the immature rat cerebellum. J Neurobiol 7:567–578
Crepel F, Delhaye-Bouchaud N, Guastavino JM, Sampaio I (1980) Multiple innervation of cerebellar Purkinje cells by climbing fibres in staggerer mutant mouse. Nature 283:483–484
Crepel F, Delhaye-Bouchaud N, Dupont JL (1981) Fate of the multiple innervation of cerebellar Purkinje cells by climbing fibers in immature control, X-irradiated and hypothyroid rats. Brain Res 227:59–71
De Zeeuw CI, Hansel C, Bian F, Koekkoek SK, van Alphen AM, Linden DJ, Oberdick J (1998) Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron 20:495–508
Dzubay JA, Otis TS (2002) Climbing fiber activation of metabotropic glutamate receptors on cerebellar purkinje neurons. Neuron 36:1159–1167
Finch EA, Augustine GJ (1998) Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites. Nature 396:753–756
Gan WB, Kwon E, Feng G, Sanes JR, Lichtman JW (2003) Synaptic dynamism measured over minutes to months: age-dependent decline in an autonomic ganglion. Nat Neurosci 6:956–960
Hansel C, de Jeu M, Belmeguenai A, Houtman SH, Buitendijk GH, Andreev D, De Zeeuw CI, Elgersma Y (2006) αCaMKII Is essential for cerebellar LTD and motor learning. Neuron 51:835–843
Hashimoto K, Kano M (2003) Functional differentiation of multiple climbing fiber inputs during synapse elimination in the developing cerebellum. Neuron 38:785–796
Hashimoto K, Kano M (2005) Postnatal development and synapse elimination of climbing fiber to Purkinje cell projection in the cerebellum. Neurosci Res 53:221–228
Hashimoto K, Watanabe M, Kurihara H, Offermanns S, Jiang H, Wu Y, Jun K, Shin HS, Inoue Y, Wu D, Simon MI, Kano M (2000) Climbing fiber synapse elimination during postnatal cerebellar development requires signal transduction involving Gαq and phospholipase C β4. Prog Brain Res 124:31–48
Hashimoto K, Ichikawa R, Takechi H, Inoue Y, Aiba A, Sakimura K, Mishina M, Hashikawa T, Konnerth A, Watanabe M, Kano M (2001) Roles of glutamate receptor δ2 subunit (GluRδ2) and metabotropic glutamate receptor subtype 1 (mGluR1) in climbing fiber synapse elimination during postnatal cerebellar development. J Neurosci 21:9701–9712
Hashimoto K, Ichikawa R, Kitamura K, Watanabe M, Kano M (2009a) Translocation of a “winner” climbing fiber to the Purkinje cell dendrite and subsequent elimination of “losers” from the soma in developing cerebellum. Neuron 63:106–118
Hashimoto K, Yoshida T, Sakimura K, Mishina M, Watanabe M, Kano M (2009b) Influence of parallel fiber-Purkinje cell synapse formation on postnatal development of climbing fiber-Purkinje cell synapses in the cerebellum. Neuroscience 162:601–611
Hirai H, Pang Z, Bao D, Miyazaki T, Li L, Miura E, Parris J, Rong Y, Watanabe M, Yuzaki M, Morgan JI (2005) Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci 8:1534–1541
Ichikawa R, Miyazaki T, Kano M, Hashikawa T, Tatsumi H, Sakimura K, Mishina M, Inoue Y, Watanabe M (2002) Distal extension of climbing fiber territory and multiple innervation caused by aberrant wiring to adjacent spiny branchlets in cerebellar Purkinje cells lacking glutamate receptor δ2. J Neurosci 22:8487–8503
Ichise T, Kano M, Hashimoto K, Yanagihara D, Nakao K, Shigemoto R, Katsuki M, Aiba A (2000) mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288:1832–1835
Ito M (1984) The cerebellum and neural control. Raven, New York
Ito-Ishida A, Miura E, Emi K, Matsuda K, Iijima T, Kondo T, Kohda K, Watanabe M, Yuzaki M (2008) Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo. J Neurosci 28:5920–5930
Johnson EM, Craig ET, Yeh HH (2007) TrkB is necessary for pruning at the climbing fibre-Purkinje cell synapse in the developing murine cerebellum. J Physiol 582:629–646
Kakizawa S, Yamasaki M, Watanabe M, Kano M (2000) Critical period for activity-dependent synapse elimination in developing cerebellum. J Neurosci 20:4954–4961
Kakizawa S, Yamada K, Iino M, Watanabe M, Kano M (2003) Effects of insulin-like growth factor I on climbing fibre synapse elimination during cerebellar development. Eur J Neurosci 17:545–554
Kano M, Hashimoto K (2009) Synapse elimination in the central nervous system. Curr Opin Neurobiol 19:154–161
Kano M, Hashimoto K, Chen C, Abeliovich A, Aiba A, Kurihara H, Watanabe M, Inoue Y, Tonegawa S (1995) Impaired synapse elimination during cerebellar development in PKCγ mutant mice. Cell 83:1223–1231
Kano M, Hashimoto K, Kurihara H, Watanabe M, Inoue Y, Aiba A, Tonegawa S (1997) Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1. Neuron 18:71–79
Kano M, Hashimoto K, Watanabe M, Kurihara H, Offermanns S, Jiang H, Wu Y, Jun K, Shin HS, Inoue Y, Simon MI, Wu D (1998) Phospholipase Cβ4 is specifically involved in climbing fiber synapse elimination in the developing cerebellum. Proc Natl Acad Sci USA 95:15724–15729
Kano M, Hashimoto K, Tabata T (2008) Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination. Phil Trans R Soc B 363:2173–2186
Kashiwabuchi N, Ikeda K, Araki K, Hirano T, Shibuki K, Takayama C, Inoue Y, Kutsuwada T, Yagi T, Kang Y et al (1995) Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR δ2 mutant mice. Cell 81:245–252
Kulik A, Nakadate K, Hagiwara A, Fukazawa Y, Lujan R, Saito H, Suzuki N, Futatsugi A, Mikoshiba K, Frotscher M, Shigemoto R (2004) Immunocytochemical localization of the α1A subunit of the P/Q-type calcium channel in the rat cerebellum. Eur J Neurosci 19:2169–2178
Kurihara H, Hashimoto K, Kano M, Takayama C, Sakimura K, Mishina M, Inoue Y, Watanabe M (1997) Impaired parallel fiber –> Purkinje cell synapse stabilization during cerebellar development of mutant mice lacking the glutamate receptor δ2 subunit. J Neurosci 17:9613–9623
Letellier M, Wehrle R, Mariani J, Lohof AM (2009) Synapse elimination in olivo-cerebellar explants occurs during a critical period and leaves an indelible trace in Purkinje cells. Proc Natl Acad Sci USA 106:14102–14107
Levenes C, Daniel H, Jaillard D, Conquet F, Crepel F (1997) Incomplete regression of multiple climbing fibre innervation of cerebellar Purkinje cells in mGluR1 mutant mice. Neuroreport 8:571–574
Lohof AM, Delhaye-Bouchaud N, Mariani J (1996) Synapse elimination in the central nervous system: functional significance and cellular mechanisms. Rev Neurosci 7:85–101
Lorenzetto E, Caselli L, Feng G, Yuan W, Nerbonne JM, Sanes JR, Buffelli M (2009) Genetic perturbation of postsynaptic activity regulates synapse elimination in developing cerebellum. Proc Natl Acad Sci USA 106:16475–16480
Mariani J, Changeux JP (1980) Multiple innervation of Purkinje cells by climbing fibers in the cerebellum of the adult staggerer mutant mouse. J Neurobiol 11:41–50
Mariani J, Changeux JP (1981) Ontogenesis of olivocerebellar relationships. I. Studies by intracellular recordings multiple innervation Purkinje cells by climbing fibers developing rat cerebellum. J Neurosci 1:696–702
Mariani J, Crepel F, Mikoshiba K, Changeux JP, Sotelo C (1977) Anatomical, physiological and biochemical studies of the cerebellum from Reeler mutant mouse. Philos Trans R Soc Lond B Biol Sci 281:1–28
Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Ito-Ishida A, Kondo T, Shigemoto R, Watanabe M, Yuzaki M (2010) Cbln1 is a ligand for an orphan glutamate receptor δ2, a bidirectional synapse organizer. Science 328:363–368
Mintz IM, Adams ME, Bean BP (1992) P-type calcium channels in rat central and peripheral neurons. Neuron 9:85–95
Miyazaki T, Hashimoto K, Shin HS, Kano M, Watanabe M (2004) P/Q-type Ca2+ channel α1A regulates synaptic competition on developing cerebellar Purkinje cells. J Neurosci 24:1734–1743
Miyazaki T, Hashimoto K, Uda A, Sakagami H, Nakamura Y, Saito SY, Nishi M, Kume H, Tohgo A, Kaneko I, Kondo H, Fukunaga K, Kano M, Watanabe M, Takeshima H (2006) Disturbance of cerebellar synaptic maturation in mutant mice lacking BSRPs, a novel brain-specific receptor-like protein family. FEBS Lett 580:4057–4064
Miyazaki T, Yamasaki M, Takeuchi T, Sakimura K, Mishina M, Watanabe M (2010) Ablation of glutamate receptor GluRδ2 in adult Purkinje cells causes multiple innervation of climbing fibers by inducing aberrant invasion to parallel fiber innervation territory. J Neurosci 30:15196–15209
Nishiyama H, Fukaya M, Watanabe M, Linden DJ (2007) Axonal motility and its modulation by activity are branch-type specific in the intact adult cerebellum. Neuron 56:472–487
Offermanns S, Hashimoto K, Watanabe M, Sun W, Kurihara H, Thompson RF, Inoue Y, Kano M, Simon MI (1997) Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking Gαq. Proc Natl Acad Sci USA 94:14089–14094
Ohtsuki G, Hirano T (2008) Bidirectional plasticity at developing climbing fiber-Purkinje neuron synapses. Eur J Neurosci 28:2393–2400
Palay SL, Chan-Palay V (1974) Cerebellar cortex. Springer, New York
Rabacchi S, Bailly Y, Delhaye-Bouchaud N, Mariani J (1992) Involvement of the N-methyl D-aspartate (NMDA) receptor in synapse elimination during cerebellar development. Science 256:1823–1825
Ribar TJ, Rodriguiz RM, Khiroug L, Wetsel WC, Augustine GJ, Means AR (2000) Cerebellar defects in Ca2+/calmodulin kinase IV-deficient mice. J Neurosci 20:RC107
Rico B, Xu B, Reichardt LF (2002) TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat Neurosci 5:225–233
Rossi F, Wiklund L, van der Want JJ, Strata P (1991) Reinnervation of cerebellar Purkinje cells by climbing fibres surviving a subtotal lesion of the inferior olive in the adult rat. I. Development of new collateral branches and terminal plexuses. J Comp Neurol 308:513–535
Roth A, Hausser M (2001) Compartmental models of rat cerebellar Purkinje cells based on simultaneous somatic and dendritic patch-clamp recordings. J Physiol 535:445–472
Scelfo B, Strata P (2005) Correlation between multiple climbing fibre regression and parallel fibre response development in the postnatal mouse cerebellum. Eur J Neurosci 21:971–978
Sherrard RM, Dixon KJ, Bakouche J, Rodger J, Lemaigre-Dubreuil Y, Mariani J (2009) Differential expression of TrkB isoforms switches climbing fiber-Purkinje cell synaptogenesis to selective synapse elimination. Dev Neurobiol 69:647–662
Song JW, Misgeld T, Kang H, Knecht S, Lu J, Cao Y, Cotman SL, Bishop DL, Lichtman JW (2008) Lysosomal activity associated with developmental axon pruning. J Neurosci 28:8993–9001
Stea A, Tomlinson WJ, Soong TW, Bourinet E, Dubel SJ, Vincent SR, Snutch TP (1994) Localization and functional properties of a rat brain α1A calcium channel reflect similarities to neuronal Q- and P-type channels. Proc Natl Acad Sci USA 91:10576–10580
Sugihara I (2005) Microzonal projection and climbing fiber remodeling in single olivocerebellar axons of newborn rats at postnatal days 4–7. J Comp Neurol 487:93–106
Sugihara I, Wu H, Shinoda Y (1999) Morphology of single olivocerebellar axons labeled with biotinylated dextran amine in the rat. J Comp Neurol 414:131–148
Sugihara I, Bailly Y, Mariani J (2000) Olivocerebellar climbing fibers in the granuloprival cerebellum: morphological study of individual axonal projections in the X-irradiated rat. J Neurosci 20:3745–3760
Takagishi Y, Hashimoto K, Kayahara T, Watanabe M, Otsuka H, Mizoguchi A, Kano M, Murata Y (2007) Diminished climbing fiber innervation of Purkinje cells in the cerebellum of myosin Va mutant mice and rats. Dev Neurobiol 67:909–923
Takayama C, Inoue Y (2004) Transient expression of GABAA receptor α2 and α3 subunits in differentiating cerebellar neurons. Brain Res Dev Brain Res 148:169–177
Takechi H, Eilers J, Konnerth A (1998) A new class of synaptic response involving calcium release in dendritic spines. Nature 396:757–760
Takeuchi T, Miyazaki T, Watanabe M, Mori H, Sakimura K, Mishina M (2005) Control of synaptic connection by glutamate receptor δ2 in the adult cerebellum. J Neurosci 25:2146–2156
Uemura T, Lee SJ, Yasumura M, Takeuchi T, Yoshida T, Ra M, Taguchi R, Sakimura K, Mishina M (2010) Trans-synaptic interaction of GluRδ2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell 141:1068–1079
Walsh MK, Lichtman JW (2003) In vivo time-lapse imaging of synaptic takeover associated with naturally occurring synapse elimination. Neuron 37:67–73
Wassef M, Chedotal A, Cholley B, Thomasset M, Heizmann CW, Sotelo C (1992) Development of the olivocerebellar projection in the rat: I. Transient biochemical compartmentation of the inferior olive. J Comp Neurol 323:519–536
Watanabe M (2008) Molecular mechanisms governing competitive synaptic wiring in cerebellar Purkinje cells. Tohoku J Exp Med 214:175–190
Watase K, Hashimoto K, Kano M, Yamada K, Watanabe M, Inoue Y, Okuyama S, Sakagawa T, Ogawa S, Kawashima N, Hori S, Takimoto M, Wada K, Tanaka K (1998) Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice. Eur J Neurosci 10:976–988
Woodward DJ, Hoffer BJ, Altman J (1974) Physiological and pharmacological properties of Purkinje cells in rat cerebellum degranulated by postnatal x-irradiation. J Neurobiol 5:283–304
Yamada K, Fukaya M, Shimizu H, Sakimura K, Watanabe M (2001) NMDA receptor subunits GluRε1, GluRε3 and GluRζ1 are enriched at the mossy fibre-granule cell synapse in the adult mouse cerebellum. Eur J Neurosci 13:2025–2036
Acknowledgments
This work has been supported in part by the Strategic Research Program for Brain Sciences (Development of Biomarker Candidates for Social Behavior), Grants-in-Aid for Scientific Research 21220006 (M.K.) and 19100005 (M.W.), and the Global COE Program (Integrative Life Science Based on the Study of Biosignaling Mechanisms) from MEXT, Japan.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media Dordrecht
About this entry
Cite this entry
Kano, M., Watanabe, M. (2013). Synaptogenesis and Synapse Elimination. In: Manto, M., Schmahmann, J.D., Rossi, F., Gruol, D.L., Koibuchi, N. (eds) Handbook of the Cerebellum and Cerebellar Disorders. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1333-8_14
Download citation
DOI: https://doi.org/10.1007/978-94-007-1333-8_14
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-1332-1
Online ISBN: 978-94-007-1333-8
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences