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New role of δ2-glutamate receptors in AMPA receptor trafficking and cerebellar function

Nature Neuroscience volume 6, pages 869–876 (2003)Cite this article

Abstract

Previous gene knockout studies have shown that the orphan glutamate receptor δ2 (GluRδ2) is critically involved in synaptogenesis between parallel fibers and Purkinje cells during development. However, the precise function of GluRδ2 and whether it is functional in the mature cerebellum remain unclear. To address these issues, we developed an antibody specific for the putative ligand-binding region of GluRδ2, and application of this antibody to cultured Purkinje cells induced AMPA receptor endocytosis, attenuated synaptic transmission and abrogated long-term depression. Moreover, injection of this antibody into the subarachnoidal supracerebellar space of adult mice caused transient cerebellar dysfunction, such as ataxic gait and poor performance in the rotorod test. These results indicate that GluRδ2 is involved in AMPA receptor trafficking and cerebellar function in adult mice.

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Figure 1: Membrane topology of the glutamate receptor and its ligand binding sites.
Figure 2: An antibody targeted to the GluRδ2 H2 region (anti-δH2) specifically recognized the extracellular region of GluRδ2.
Figure 3: Ligation by anti-δH2 reduced the current through the GluRδ2Lc channel.
Figure 4: Treatment with anti-δH2 attenuated synaptic transmission with affecting neither eEPSC kinetics nor PPF.
Figure 5: Application of anti-δH2 blocked induction of LTD.
Figure 6: Treatment of Purkinje cells with anti-δH2 decreased the levels of synaptic AMPA receptors.
Figure 7: Cerebellar exposure to anti-δH2 impaired motor coordination.

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Acknowledgements

We thank M. Mishina for the GluRδ2−/− mice, I. Tarnawa for GYKI53655, J. Boulter for the GluRδ2 cDNAs, M. Ito for encouragement and T. Curran for critically reading the manuscript. This work was supported in part by the Uehara Memorial Foundation (H.H.), US National Institutes of Health grant NS36925, Cancer Center Support Grant CA 21765 and the American Lebanese Syrian Associated Charities (M.Y.).

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Author notes

  1. Hirokazu Hirai

    Present address: Kobe University, Graduate School of Medicine and PRESTO, Japan Science and Technology Corporation (JST), 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

Authors and Affiliations

  1. Laboratory for Memory & Learning, RIKEN Brain Science Institute, Saitama, 351-0198, Japan

    Hirokazu Hirai, Thomas Launey, Sumiko Mikawa & Takashi Torashima

  2. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, 38105, Tennessee, USA

    Hirokazu Hirai, Takashi Torashima & Michisuke Yuzaki

  3. Laboratory for Neurophysiology, Toyohashi University of Technology, Toyohashi, 441-8580, Japan

    Dai Yanagihara, Tsuyoshi Kasaura & Akihiro Miyamoto

  4. CREST, Japan Science and Technology Corporation (JST), Saitama, 332-0012, Japan

    Dai Yanagihara

  5. Department of Physiology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Michisuke Yuzaki

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Supplementary information

Supplementary Video 1.

Mice injected with a control antibody targeted to the non-S1 N-terminal region of GluR2 showed normal motor coordination 1 h after treatment. (MPG 1328 kb)

Supplementary Video 2.

Mice injected with anti-δH2 showed motor discoordination 1 h after treatment. (MPG 919 kb)

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Hirai, H., Launey, T., Mikawa, S. et al. New role of δ2-glutamate receptors in AMPA receptor trafficking and cerebellar function. Nat Neurosci 6, 869–876 (2003). https://doi.org/10.1038/nn1086

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