Cbln1 is essential for synaptic integrity and plasticity in the cerebellum


Cbln1 is a cerebellum-specific protein of previously unknown function that is structurally related to the C1q and tumor necrosis factor families of proteins. We show that Cbln1 is a glycoprotein secreted from cerebellar granule cells that is essential for three processes in cerebellar Purkinje cells: the matching and maintenance of pre- and postsynaptic elements at parallel fiber–Purkinje cell synapses, the establishment of the proper pattern of climbing fiber–Purkinje cell innervation, and induction of long-term depression at parallel fiber–Purkinje cell synapses. Notably, the phenotype of cbln1-null mice mimics loss-of-function mutations in the orphan glutamate receptor, GluRδ2, a gene selectively expressed in Purkinje neurons. Therefore, Cbln1 secreted from presynaptic granule cells may be a component of a transneuronal signaling pathway that controls synaptic structure and plasticity.

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Figure 1: Cbln1 is a glycoprotein secreted from cerebellar granule cells.
Figure 2: Generation of cbln1 null mice.
Figure 3: Ataxic phenotype of cbln1-null mice.
Figure 4: Neuroanatomical analysis of cbln1−/− mice.
Figure 5: Reduced efficiency of PF–Purkinje cell synaptic transmission in cbln1−/− mice.
Figure 6: Appearance of free spines and abnormal PF–Purkinje cell synapses in cbln1−/− mice.
Figure 7: Multiple CF innervation of Purkinje cells in cbln1−/− mice.
Figure 8: LTD is deficient in Purkinje cells of cbln1−/− mice.

Accession codes




  1. 1

    Urade, Y., Oberdick, J., Molinar-Rode, R. & Morgan, J.I. Precerebellin is a cerebellum-specific protein with similarity to the globular domain of complement C1q B chain. Proc. Natl. Acad. Sci. USA 88, 1069–1073 (1991).

  2. 2

    Pang, Z., Zuo, J. & Morgan, J.I. Cbln3, a novel member of the precerebellin family that binds specifically to Cbln1. J. Neurosci. 20, 6333–6339 (2000).

  3. 3

    Slemmon, J.R., Blacher, R., Danho, W., Hempstead, J.L. & Morgan, J.I. Isolation and Sequencing of Two Cerebellum-Specific Peptides. Proc. Natl. Acad. Sci. USA 81, 6866–6870 (1984).

  4. 4

    Kishore, U. et al. C1q and tumor necrosis factor superfamily: modularity and versatility. Trends Immunol. 25, 551–561 (2004).

  5. 5

    Beattie, E.C. et al. Control of synaptic strength by glial TNFalpha. Science 295, 2282–2285 (2002).

  6. 6

    Mugnaini, E., Dahl, A.L. & Morgan, J.I. Cerebellin is a postsynaptic neuropeptide. Synapse 2, 125–138 (1988).

  7. 7

    Hawkes, R. & Herrup, K. Aldolase C/zebrin II and the regionalization of the cerebellum. J. Mol. Neurosci. 6, 147–158 (1995).

  8. 8

    Ichikawa, R. et al. Distal extension of climbing fiber territory and multiple innervation caused by aberrant wiring to adjacent spiny branchlets in cerebellar Purkinje cells lacking glutamate receptor delta 2. J. Neurosci. 22, 8487–8503 (2002).

  9. 9

    Crepel, F., Mariani, J. & Delhaye-Bouchaud, N. Evidence for a multiple innervation of Purkinje cells by climbing fibers in the immature rat cerebellum. J. Neurobiol. 7, 567–578 (1976).

  10. 10

    Kano, M. et al. Impaired synapse elimination during cerebellar development in PKC gamma mutant mice. Cell 83, 1223–1231 (1995).

  11. 11

    Kano, M. et al. Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1. Neuron 18, 71–79 (1997).

  12. 12

    Ito, M. Long-term depression. Annu. Rev. Neurosci. 12, 85–102 (1989).

  13. 13

    Lev-Ram, V., Jiang, T., Wood, J., Lawrence, D.S. & Tsien, R.Y. Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. Neuron 18, 1025–1038 (1997).

  14. 14

    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. 19, 2765–2774 (2000).

  15. 15

    Wang, Y.T. & Linden, D.J. Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron 25, 635–647 (2000).

  16. 16

    Watanabe, D. et al. Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination. Cell 95, 17–27 (1998).

  17. 17

    Sotelo, C. Cerebellar synaptogenesis: what we can learn from mutant mice. J. Exp. Biol. 153, 225–249 (1990).

  18. 18

    Rhyu, I.J., Abbott, L.C., Walker, D.B. & Sotelo, C. An ultrastructural study of granule cell/Purkinje cell synapses in tottering (tg/tg), leaner (tg(la)/tg(la)) and compound heterozygous tottering/leaner (tg/tg(la)) mice. Neuroscience 90, 717–728 (1999).

  19. 19

    Chen, C. et al. Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC gamma mutant mice. Cell 83, 1233–1242 (1995).

  20. 20

    Benoit, P., Delhaye-Bouchaud, N., Changeux, J.P. & Mariani, J. Stability of multiple innervation of Purkinje cells by climbing fibers in the agranular cerebellum of old rats X-irradiated at birth. Brain Res. 316, 310–313 (1984).

  21. 21

    Kashiwabuchi, N. et al. Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. Cell 81, 245–252 (1995).

  22. 22

    Kurihara, H. et al. Impaired parallel fiber → Purkinje cell synapse stabilization during cerebellar development of mutant mice lacking the glutamate receptor delta2 subunit. J. Neurosci. 17, 9613–9623 (1997).

  23. 23

    Hashimoto, K. et al. Roles of glutamate receptor delta 2 subunit (GluRdelta 2) and metabotropic glutamate receptor subtype 1 (mGluR1) in climbing fiber synapse elimination during postnatal cerebellar development. J. Neurosci. 21, 9701–9712 (2001).

  24. 24

    Lalouette, A., Lohof, A., Sotelo, C., Guenet, J. & Mariani, J. Neurobiological effects of a null mutation depend on genetic context: comparison between two hotfoot alleles of the delta-2 ionotropic glutamate receptor. Neuroscience 105, 443–455 (2001).

  25. 25

    Yuzaki, M. The delta2 glutamate receptor: 10 years later. Neurosci. Res. 46, 11–22 (2003).

  26. 26

    Morando, L., Cesa, R., Rasetti, R., Harvey, R. & Strata, P. Role of glutamate delta -2 receptors in activity-dependent competition between heterologous afferent fibers. Proc. Natl. Acad. Sci. USA 98, 9954–9959 (2001).

  27. 27

    Lomeli, H. et al. The rat delta-1 and delta-2 subunits extend the excitatory amino acid receptor family. FEBS Lett. 315, 318–322 (1993).

  28. 28

    Kavety, B., Jenkins, N.A., Fletcher, C.F., Copeland, N.G. & Morgan, J.I. Genomic structure and mapping of precerebellin and a precerebellin-related gene. Brain Res. Mol. Brain Res. 27, 152–156 (1994).

  29. 29

    Furuya, S., Makino, A. & Hirabayashi, Y. An improved method for culturing cerebellar Purkinje cells with differentiated dendrites under a mixed monolayer setting. Brain Res. Brain Res. Protoc. 3, 192–198 (1998).

  30. 30

    Morgan, J.I. et al. Cerebellin and related postsynaptic peptides in the brain of normal and neurodevelopmentally mutant vertebrates. Synapse 2, 117–124 (1988).

  31. 31

    Ziai, M.R., Sangameswaran, L., Hempstead, J.L., Danho, W. & Morgan, J.I. An immunochemical analysis of the distribution of a brain-specific polypeptide, PEP-19. J. Neurochem. 51, 1771–1776 (1988).

  32. 32

    Oberdick, J., Smeyne, R.J., Mann, J.R., Zackson, S. & Morgan, J.I. A promoter that drives transgene expression in cerebellar Purkinje and retinal bipolar neurons. Science 248, 223–226 (1990).

  33. 33

    Kohda, K., Wang, Y. & Yuzaki, M. Mutation of a glutamate receptor motif reveals its role in gating and delta2 receptor channel properties. Nat. Neurosci. 3, 315–322 (2000).

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We thank M. Mishina for the GluRδ2−/− mice, R. Hawkes for the Zebrin II antiserum and T. Torashima for technical assistance. Supported in part by US National Institutes of Health grants ES10772, NS040361, NS040749, NS042828 (J.M.), the Toray Science and Technology Grant (M.Y.), Japanese Grants-in-Aid for Scientific Research (M.Y.), Cancer Center Support Core Grant CA 21765 (J.M., M.Y.) and the American Lebanese Syrian Associated Charities (J.M., M.Y.).

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Correspondence to Michisuke Yuzaki or James I Morgan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Lack of cbln1 expression in the inferior olivary nucleus. (PDF 1324 kb)

Supplementary Fig. 2

Ataxic phenotype of cbln1-null mice. (PDF 732 kb)

Supplementary Fig. 3

Electron microscopic analysis of parallel fiber terminals. (PDF 542 kb)

Supplementary Fig. 4

The pattern of inhibitory innervation in cbln1−/− mice. (PDF 2694 kb)

Supplementary Fig. 5

Depiction of the impairments of Purkinje cells in cbln1−/− cerebellum. (PDF 245 kb)

Supplementary Fig. 6

Frequency of free Purkinje cell spines in mice lacking both GluRδ2 and Cbln1. (PDF 327 kb)

Supplementary Table 1

Volume measurements of cerebella from wild-type and cbln1−/− mice at 1 month of age. (PDF 70 kb)

Supplementary Table 2

Passive membrane properties of cerebellar neurons. (PDF 70 kb)

Supplementary Table 3

Basic properties of CF- and PF-EPSCs in cbln1−/− mice. (PDF 54 kb)

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Hirai, H., Pang, Z., Bao, D. et al. Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci 8, 1534–1541 (2005). https://doi.org/10.1038/nn1576

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