Cbln1 is essential for synaptic integrity and plasticity in the cerebellum

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.

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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.

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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.).

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Correspondence to Michisuke Yuzaki or James I Morgan.

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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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