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The Journal of Neuroscience, June 4, 2008, 28(23):5920-5930; doi:10.1523/JNEUROSCI.1030-08.2008

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Development/Plasticity/Repair
Cbln1 Regulates Rapid Formation and Maintenance of Excitatory Synapses in Mature Cerebellar Purkinje Cells In Vitro and In Vivo

Aya Ito-Ishida,¹ Eriko Miura,² Kyoichi Emi,¹ Keiko Matsuda,¹ Takatoshi Iijima,¹ Tetsuro Kondo,^1,3 Kazuhisa Kohda,¹ Masahiko Watanabe,² and Michisuke Yuzaki¹

¹Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan, ²Department of Anatomy, School of Medicine, Hokkaido University, Sapporo 060-8638, Japan, and ³Molecular Neurophysiology, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8566, Japan

Correspondence should be addressed to Michisuke Yuzaki, Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: myuzaki{at}a5.keio.jp

Although many synapse-organizing molecules have been identified in vitro, their functions in mature neurons in vivo have been mostly unexplored. Cbln1, which belongs to the C1q/tumor necrosis factor superfamily, is the most recently identified protein involved in synapse formation in the mammalian CNS. In the cerebellum, Cbln1 is predominantly produced and secreted from granule cells; cbln1-null mice show ataxia and a severe reduction in the number of synapses between Purkinje cells and parallel fibers (PFs), the axon bundle of granule cells. Here, we show that application of recombinant Cbln1 specifically and reversibly induced PF synapse formation in dissociated cbln1-null Purkinje cells in culture. Cbln1 also rapidly induced electrophysiologically functional and ultrastructurally normal PF synapses in acutely prepared cbln1-null cerebellar slices. Furthermore, a single injection of recombinant Cbln1 rescued severe ataxia in adult cbln1-null mice in vivo by completely, but transiently, restoring PF synapses. Therefore, Cbln1 is a unique synapse organizer that is required not only for the normal development of PF-Purkinje cell synapses but also for their maintenance in the mature cerebellum both in vitro and in vivo. Furthermore, our results indicate that Cbln1 can also rapidly organize new synapses in adult cerebellum, implying its therapeutic potential for cerebellar ataxic disorders.

Key words: cerebellum; Purkinje cell; synaptogenesis; mouse; cerebellin; C1q; parallel fiber

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Received March 8, 2008; revised April 15, 2008; accepted April 26, 2008.

Correspondence should be addressed to Michisuke Yuzaki, Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: myuzaki{at}a5.keio.jp

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