Article | Published:

Cbln1 is essential for synaptic integrity and plasticity in the cerebellum

Nature Neuroscience volume 8, pages 15341541 (2005) | Download Citation

Subjects

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

GenBank/EMBL/DDBJ

References

  1. 1.

    , , & 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.

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

  3. 3.

    , , , & Isolation and Sequencing of Two Cerebellum-Specific Peptides. Proc. Natl. Acad. Sci. USA 81, 6866–6870 (1984).

  4. 4.

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

  5. 5.

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

  6. 6.

    , & Cerebellin is a postsynaptic neuropeptide. Synapse 2, 125–138 (1988).

  7. 7.

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

  8. 8.

    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.

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

  10. 10.

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

  11. 11.

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

  12. 12.

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

  13. 13.

    , , , & Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. Neuron 18, 1025–1038 (1997).

  14. 14.

    , , & Disruption of AMPA receptor GluR2 clusters following long-term depression induction in cerebellar Purkinje neurons. EMBO J. 19, 2765–2774 (2000).

  15. 15.

    & Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron 25, 635–647 (2000).

  16. 16.

    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.

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

  18. 18.

    , , & 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.

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

  20. 20.

    , , & 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.

    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.

    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.

    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.

    , , , & 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.

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

  26. 26.

    , , , & 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.

    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.

    , , , & Genomic structure and mapping of precerebellin and a precerebellin-related gene. Brain Res. Mol. Brain Res. 27, 152–156 (1994).

  29. 29.

    , & 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.

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

  31. 31.

    , , , & An immunochemical analysis of the distribution of a brain-specific polypeptide, PEP-19. J. Neurochem. 51, 1771–1776 (1988).

  32. 32.

    , , , & A promoter that drives transgene expression in cerebellar Purkinje and retinal bipolar neurons. Science 248, 223–226 (1990).

  33. 33.

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

Download references

Acknowledgements

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.).

Author information

Author notes

    • Hirokazu Hirai
    • , Zhen Pang
    •  & Michisuke Yuzaki

    Current addresses: Advanced Science Research Center, Kanazawa University, PRESTO, Japan Science and Technology Agency, Kanazawa 920-8640, Japan (H.H.); Roche Palo Alto, 3431 Hillview Ave., R2-101 Palo Alto, California 94304-1320 USA (Z.P.) and Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan (M.Y.).

    • Hirokazu Hirai
    •  & Zhen Pang

    These authors contributed equally to this work.

Affiliations

  1. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, MS 323, Memphis, Tennessee 38105-2794, USA.

    • Hirokazu Hirai
    • , Zhen Pang
    • , Dashi Bao
    • , Leyi Li
    • , Jennifer Parris
    • , Yongqi Rong
    • , Michisuke Yuzaki
    •  & James I Morgan
  2. Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.

    • Taisuke Miyazaki
    • , Eriko Miura
    •  & Masahiko Watanabe

Authors

  1. Search for Hirokazu Hirai in:

  2. Search for Zhen Pang in:

  3. Search for Dashi Bao in:

  4. Search for Taisuke Miyazaki in:

  5. Search for Leyi Li in:

  6. Search for Eriko Miura in:

  7. Search for Jennifer Parris in:

  8. Search for Yongqi Rong in:

  9. Search for Masahiko Watanabe in:

  10. Search for Michisuke Yuzaki in:

  11. Search for James I Morgan in:

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michisuke Yuzaki or James I Morgan.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Lack of cbln1 expression in the inferior olivary nucleus.

  2. 2.

    Supplementary Fig. 2

    Ataxic phenotype of cbln1-null mice.

  3. 3.

    Supplementary Fig. 3

    Electron microscopic analysis of parallel fiber terminals.

  4. 4.

    Supplementary Fig. 4

    The pattern of inhibitory innervation in cbln1−/− mice.

  5. 5.

    Supplementary Fig. 5

    Depiction of the impairments of Purkinje cells in cbln1−/− cerebellum.

  6. 6.

    Supplementary Fig. 6

    Frequency of free Purkinje cell spines in mice lacking both GluRδ2 and Cbln1.

  7. 7.

    Supplementary Table 1

    Volume measurements of cerebella from wild-type and cbln1−/− mice at 1 month of age.

  8. 8.

    Supplementary Table 2

    Passive membrane properties of cerebellar neurons.

  9. 9.

    Supplementary Table 3

    Basic properties of CF- and PF-EPSCs in cbln1−/− mice.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn1576

Further reading