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Glutamate-Receptor-Like Molecule GluRδ2 Involved in Synapse Formation at Parallel Fiber-Purkinje Neuron Synapses

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Abstract

Glutamate-receptor-like molecule δ2 (GluRδ2, GluD2) has been classified as an ionotropic glutamate receptor subunit. It is selectively expressed on the postsynaptic membrane at parallel fiber-Purkinje neuron synapses in the cerebellum. Mutant mice deficient in GluRδ2 show impaired synaptic plasticity, the decrease in the number of parallel fiber-Purkinje neuron synapses, multiple innervation of climbing fibers on a Purkinje neuron, and defects in motor control and learning. Thus, GluRδ2 plays crucial roles in the cerebellar function. Recent studies on GluRδ2 have shown that it has synaptogenic activity. GluRδ2 expressed in a non-neuronal cell induces presynaptic differentiation of granule neurons in a co-culture preparation. This synaptogenic activity depends on an extracellular N-terminal leucine/isoleucine/valine binding protein-like domain of GluRδ2. GluRδ2 plays critical roles in formation, maturation, and/or maintenance of granule neuron–Purkinje neuron synapses.

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References

  1. Hollmann M, Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci. 1994;17:31–108.

    Article  PubMed  CAS  Google Scholar 

  2. Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol. 1997;37:205–37.

    Article  CAS  Google Scholar 

  3. Sobolevski AI, Rosconi MP, Gouaux E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 2009;462:745–56.

    Article  Google Scholar 

  4. Takayama C, Nakagawa S, Watanabe M, Mishina M, Inoue Y. Light- and electron-microscopic localization of the glutamate receptor channel δ2 subunit in the mouse Purkinje cell. Neurosci Lett. 1995;188:89–92.

    Article  PubMed  CAS  Google Scholar 

  5. Hirano T, Kasono K, Araki K, Shinozuka K, Mishina M. Involvement of the glutamate receptor δ2 subunit in the long-term depression of glutamate responsiveness in cultured rat Purkinje cells. Neurosci Lett. 1994;182:172–6.

    Article  PubMed  CAS  Google Scholar 

  6. Kashiwabuchi N, Ikeda K, Araki K, Hirano T, Shibuki K, Takayama C, et al. Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR δ2 mutant mice. Cell. 1995;81:245–52.

    Article  PubMed  CAS  Google Scholar 

  7. Funabiki K, Mishina M, Hirano T. Retarded vestibular compensation in mutant mice deficient in δ2 glutamate receptor subunit. NeuroReport. 1995;7:189–92.

    PubMed  CAS  Google Scholar 

  8. Kishimoto Y, Kawahara S, Suzuki M, Mori H, Mishina M, Kirino Y. Classical eyeblink conditioning in glutamate receptor subunit δ2 mutant mice is impaired in the delay paradigm but not in the trace paradigm. Eur J Neurosci. 2001;13:1249–53.

    Article  PubMed  CAS  Google Scholar 

  9. Katoh A, Yoshida T, Himeshima Y, Mishina M, Hirano T. Defective control and adaptation of reflex eye movements in mutant mice deficient in either the glutamate receptor δ2 subunit or Purkinje cells. Eur J Neurosci. 2005;21:1315–26.

    Article  PubMed  Google Scholar 

  10. Yoshida T, Katoh A, Ohtsuki G, Mishina M, Hirano T. Oscillating Purkinje neuron activity causing involuntary eye movement in a mutant mouse deficient in the glutamate receptor δ2 subunit. J Neurosci. 2004;24:2440–8.

    Article  PubMed  CAS  Google Scholar 

  11. Yawata S, Tsuchida H, Kengaku M, Hirano T. Membrane-proximal region of GluRδ2 is critical for LTD and interaction with PICK1 in a cerebellar Purkinje neuron. J Neurosci. 2006;26:3626–33.

    Article  PubMed  CAS  Google Scholar 

  12. Kohda K, Kakegawa W, Matsuda S, Nakagami R, Kakiya N, Yuzaki M. The extreme C-terminus of GluRδ2 is essential for induction of long-term depression in cerebellar slices. Eur J Neurosci. 2007;25:1357–62.

    Article  PubMed  Google Scholar 

  13. Uemura T, Kakizawa S, Yamasaki M, Sakimura K, Watanabe M, Iino M, et al. Regulation of long-term depression and climbing fiber territory by glutamate receptor δ2 at parallel fiber synapses through its C-terminal domain in cerebellar Purkinje cells. J Neurosci. 2007;27:12096–108.

    Article  PubMed  CAS  Google Scholar 

  14. Uemura T, Mishina M. The amino-terminal domain of glutamate receptor δ2 triggers presynaptic differentiation. Biochem Biophys Res Commun. 2008;377:1315–9.

    Article  PubMed  CAS  Google Scholar 

  15. Kuroyanagi T, Yokoyama M, Hirano T. Postsynaptic glutamate receptor δ family contributes to presynaptic terminal differentiation and establishment of synaptic transmission. Proc Natl Acad Sci U S A. 2009;106:4912–6.

    Article  PubMed  CAS  Google Scholar 

  16. Kakegawa W, Miyazaki T, Kohda K, Matsuda K, Emi K, Motohashi J, et al. The N-terminal domain of GluD2 (GluRδ2) recruits presynaptic terminals and regulates synaptogenesis in the cerebellum in vivo. J Neurosci. 2009;29:5738–48.

    Article  PubMed  CAS  Google Scholar 

  17. Mandolesi G, Autuori E, Cesa R, Premoselli F, Cesare P, Strata P. GluRδ2 expression in the mature cerebellum of hotfoot mice promotes parallel fiber synaptogenesis and axonal competition. PLoS One. 2009;4:e5243.

    Article  PubMed  Google Scholar 

  18. Torashima T, Iizuka A, Horiuchi H, Mitsumura K, Yamasaki M, Koyama C, et al. Rescue of abnormal phenotypes in δ2 glutamate receptor-deficient mice by the extracellular N-terminal and intracellular C-terminal domains of the δ2 glutamate receptor. Eur J Neurosci. 2009;30:355–65.

    Article  PubMed  Google Scholar 

  19. Hirano T. Cerebellar regulation mechanisms learned from studies on GluRδ2, a unique glutamate-receptor-related molecule specifically expressed at parallel fiber-Purkinje cell synapses. Mol Neurobiol. 2006;33:1–16.

    Article  PubMed  CAS  Google Scholar 

  20. Mandolesi G, Cesa R, Autuori E, Strata P. An orphan ionotropic glutamate receptor: the δ2 subunit. Neurosci. 2009;158:67–77.

    Article  CAS  Google Scholar 

  21. Yuzaki M. New (but old) molecules regulating synaptic integrity and plasticity: Cbln1 and the δ2 glutamate receptor. Neurosci. 2009;162:633–43.

    Article  CAS  Google Scholar 

  22. Araki K, Meguro H, Kushiya E, Takayama C, Inoue Y, Mishina M. Selective expression of the glutamate receptor channel δ2 subunit in cerebellar Purkinje cells. Biochem Biophys Res Commun. 1993;197:1267–76.

    Article  PubMed  CAS  Google Scholar 

  23. Lomeli H, Sprengel R, Laurie DJ, Kohr G, Herb A, Seeburg P, et al. The rat delta-1 and delta-2 subunits extend the excitatory amino acid receptor family. FEBS Lett. 1993;315:318–22.

    Article  PubMed  CAS  Google Scholar 

  24. Hirai H, Matsuda S. Interaction of the C-terminal domain of δ glutamate receptor with spectrin in the dendritic spines of cultured Purkinje cells. Neurosci Res. 1999;34:281–7.

    Article  PubMed  CAS  Google Scholar 

  25. Roche KW, Ly CD, Petralia RS, Wang YX, McGee AW, Bredt DS, et al. Postsynaptic density-93 interacts with the δ2 glutamate receptor subunit at parallel fiber synapses. J Neurosci. 1999;19:3926–34.

    PubMed  CAS  Google Scholar 

  26. Hironaka K, Umemori H, Tezuka T, Mishina M, Yamamoto T. The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor δ2 and ε subunits. J Biol Chem. 2000;275:16167–73.

    Article  PubMed  CAS  Google Scholar 

  27. Miyagi Y, Yamashita T, Fukaya M, Sonoda T, Okuno T, Yamada K, et al. Delphilin: a novel PDZ and forming homology domain-containing protein that synaptically colocalizes and interacts with glutamate receptor δ2 subunit. J Neurosci. 2002;22:803–14.

    PubMed  CAS  Google Scholar 

  28. Yue Z, Horton A, Bravin M, Dejager PL, Selimi F, Heinz N. A novel protein complex linking the δ2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice. Neuron. 2002;35:921–33.

    Article  PubMed  CAS  Google Scholar 

  29. Uemura T, Mori H, Mishina M. Direct interaction of GluRδ2 with Shank scaffold proteins in cerebellar Purkinje cells. Mol Cell Neurosci. 2004;26:330–41.

    Article  PubMed  CAS  Google Scholar 

  30. Yap CC, Murate M, Kishigami S, Muto Y, Kishida H, Hashikawa T, et al. Adaptor protein complex-4 (AP-4) is expressed in the central nervous system neurons and interacts with glutamate receptor δ2. Mol Cell Neurosci. 2003;24:283–95.

    Article  PubMed  CAS  Google Scholar 

  31. Ly CD, Roche KW, Lee H, Wenthold RJ. Identification of rat EMAP, a δ-glutamate receptor binding protein. Biochem Biophys Res Commun. 2002;291:85–90.

    Article  PubMed  CAS  Google Scholar 

  32. Yap CC, Muto Y, Kishida H, Hashikawa T, Yano R. PKC regulates the δ2 glutamate receptor interaction with S-SCAM/MAGI-2 protein. Biochem Biophys Res Commun. 2003;301:1122–8.

    Article  PubMed  CAS  Google Scholar 

  33. Bergersen L, Waerhaug O, Helm J, Thomas M, Laake P, Davies AJ. et al A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is co-localized with δ-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses. Exp Brain Res. 2001;136:523–34.

    Article  PubMed  CAS  Google Scholar 

  34. Hung AY, Sheng M. PDZ domains: structural modules for protein complex assembly. J Biol Chem. 2002;277:5699–702.

    Article  PubMed  CAS  Google Scholar 

  35. Hirano T, Kasono K, Araki K, Mishina M. Suppression of LTD in cultured Purkinje cells deficient in the glutamate receptor δ2 subunit. NeuroReport. 1995;6:524–6.

    Article  PubMed  CAS  Google Scholar 

  36. Takeuchi T, Miyazaki T, Watanabe M, Mori H, Sakimura K, Mishina M. Control of synaptic connection by glutamate receptor δ2 in the adult cerebellum. J Neurosci. 2005;25:2146–56.

    Article  PubMed  CAS  Google Scholar 

  37. Kurihara H, Hashimoto K, Kano M, Takayama C, Sakimura K, Mishina M, et al. Impaired parallel fiber-Purkinje cell synapse stabilization during cerebellar development of mutant mice lacking the glutamate receptor δ2 subunit. J Neurosci. 1997;17:9613–23.

    PubMed  CAS  Google Scholar 

  38. Hashimoto K, Kano M. Functional differentiation of multiple climbing fiber inputs during synapse elimination in the developing cerebellum. Neuron. 2003;38:785–96.

    Article  PubMed  CAS  Google Scholar 

  39. Hashimoto K, Ichikawa R, Takechi H, Inoue Y, Aiba A, Sakimura K, et al. Roles of glutamate receptor δ2 subunit (GluRδ2) and metabotropic glutamate receptor subtype 1 (mGluR1) in climbing fiber synapse elimination during postnatal cerebellar development. J Neurosci. 2001;21:9701–12.

    PubMed  CAS  Google Scholar 

  40. Ichikawa R, Miyazaki T, Kano M, Hashikawa T, Tatsumi H, Sakimura K, 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 δ2. J Neurosci. 2002;22:8487–503.

    PubMed  CAS  Google Scholar 

  41. Kano M, Hashimoto K, Chen C, Abeliovich A, Aiba A, Kurihara H, et al. Impaired synapse elimination during cerebellar development in PKCγ mutant mice. Cell. 1995;83:1223–31.

    Article  PubMed  CAS  Google Scholar 

  42. Offermans S, Hashimoto K, Watanabe M, Sun W, Kurihara H, Thompson RF, et al. Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking Gαq. Proc Natl Acad Sci U S A. 1997;94:14089–94.

    Article  Google Scholar 

  43. Kano M, Hashimoto K, Watanabe M, Kurihara H, Offermanns S, Jiang H, et al. Phospholipase Cβ4 is specifically involved in climbing fiber synapse elimination in the developing cerebellum. Proc Natl Acad Sci U S A. 1998;95:15724–9.

    Article  PubMed  CAS  Google Scholar 

  44. Morando L, Cesa R, Rasetti R, Harvey R, Strata P. Role of glutamate δ2 receptors in activity-dependent competition between heterologous afferent fibers. Proc Natl Acad Sci U S A. 2001;98:9954–9.

    Article  PubMed  CAS  Google Scholar 

  45. Scheiffele P, Fan J, Choih J, Fetter R, Serafini T. Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell. 2000;101:657–69.

    Article  PubMed  CAS  Google Scholar 

  46. Sudhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455:903–11.

    Article  PubMed  Google Scholar 

  47. Biederer T, Sara Y, Mozhayeva M, Atasoy D, Liu X, Kavalali ET, et al. SynCAM, a synaptic adhesion molecule that drives synaptic assembly. Science. 2002;297:1525–31.

    Article  PubMed  CAS  Google Scholar 

  48. Kim S, Burette A, Chung HS, Kwon SK, Woo J, Lee HW, et al. NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation. Nat Neurosci. 2006;9:1294–301.

    Article  PubMed  CAS  Google Scholar 

  49. Kayser MS, McClelland AC, Hughes EG, Dalva MB. Intracellular and trans-synaptic regulation of glutamatergic synaptogenesis by EphB receptors. J Neurosci. 2006;26:12152–64.

    Article  PubMed  CAS  Google Scholar 

  50. Linhoff MW, Lauren J, Cassidy RM, Dobie FA, Takahashi H, Nygaard HB, et al. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron. 2009;61:734–49.

    Article  PubMed  CAS  Google Scholar 

  51. Gerrow K, Husseini AE. Cell adhesion molecules at the synapse. Front Biosci. 2006;11:2400–19.

    Article  PubMed  CAS  Google Scholar 

  52. Ko J, Fuccillo MV, Malenka RC, Sudhof TC. LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation. Neuron. 2009;64:791–8.

    Article  PubMed  CAS  Google Scholar 

  53. de Wit J, Sylwestrak E, O’Sullivan ML, Otto S, Tiglio K, Savas JN, et al. LRRTM2 interacts with neurexin1 and regulates excitatory synapse formation. Neuron. 2009;64:799–806.

    Article  PubMed  Google Scholar 

  54. Woo J, Kwon S, Kim E. The NGL family of leucine-rich repeat-containing synaptic adhesion molecules. Mol Cell Neurosci. 2009;42:1–10.

    Article  PubMed  CAS  Google Scholar 

  55. Martinez A, Soriano E. Functions of ephrin/Eph interactions in the development of the nervous system: emphasis on the hippocampal system. Brain Res Rev. 2005;49:211–26.

    Article  PubMed  CAS  Google Scholar 

  56. Hirai H, Pang Z, Bao D, Miyazaki T, Li L, Miura E, et al. Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci. 2005;8:1534–41.

    Article  PubMed  CAS  Google Scholar 

  57. Ito-Ishida A, Miura E, Emi K, Matsuda K, Iijima T, Kondo T, et al. Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo. J Neurosci. 2008;28:5920–30.

    Article  PubMed  CAS  Google Scholar 

  58. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459:569–73.

    Article  PubMed  CAS  Google Scholar 

  59. Shimokaze T, Kato M, Yoshimura Y, Takahashi Y, Hayasaka K. A case of acute cerebellitis accompanied by autoantibodies against glutamate receptor delta2. Brain Dev. 2007;29:224–6.

    Article  PubMed  Google Scholar 

  60. Shiihara T, Kato M, Konno A, Takahashi Y, Hayasaka K. Acute cerebellar ataxia and consecutive cerebellitis produced by glutamate receptor delta2 autoantibody. Brain Dev. 2007;29:254–6.

    Article  PubMed  Google Scholar 

  61. Matsuda S, Yuzaki M. Mutation in hotfoot-4J mice results in retention of δ2 glutamate receptors in ER. Eur J Neurosci. 2002;16:1507–16.

    Article  PubMed  Google Scholar 

  62. Naur P, Hansen KB, Kristensen AS, Dravid SM, Pickering DS, Olsen L, et al. Ionotropic glutamate-like receptor δ2 binds D-serine and glycine. Proc Natl Acad Sci U S A. 2007;104:14116–21.

    Article  PubMed  CAS  Google Scholar 

  63. Hirai H, Launey T, Mikawa S, Torashima T, Yanagihara D, Kasaura T, et al. New role of δ2-glutamate receptors in AMPA receptor trafficking and cerebellar function. Nat Neurosci. 2003;6:869–76.

    Article  PubMed  CAS  Google Scholar 

  64. Kina S, Tezuka T, Kusakawa S, Kishimoto Y, Kakizawa S, Hashimoto K, et al. Involvement of protein-tyrosine phosphatase PTPMEG in motor learning and cerebellar long-term depression. Eur J Neurosci. 2007;26:2269–78.

    Article  PubMed  Google Scholar 

  65. Takeuchi T, Ohtsuki G, Yoshida T, Fukaya M, Wainai T, Yamashita M, et al. Enhancement of both long-term depression induction and optokinetic response adaptation in mice lacking delphilin. PLoS One. 2008;3:e2297.

    Article  PubMed  Google Scholar 

  66. Jung S, Kim J, Kwon OB, Jung JH, An K, Jeong AY, et al. Input-specific synaptic plasticity in the amygdala is regulated by neuroligin-1 via postsynaptic NMDA receptors. Proc Natl Acad Sci U S A. 2010;107:4710–5.

    Article  PubMed  CAS  Google Scholar 

  67. Takasu MA, Dalva MB, Zigmond RE, Greenberg ME. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science. 2002;295:491–5.

    Article  PubMed  CAS  Google Scholar 

  68. Gruwald IC, Korte M, Wolfer D, Wilkinson GA, Unsicker K, Lipp H, et al. Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron. 2001;32:1027–40.

    Article  Google Scholar 

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Acknowledgments

I thank Drs. S. Kawaguchi and Y. Tagawa, Mr. T. Kuroyanagi, Ms. M. Yokoyama, and M. Yamashita for their helpful comments on the manuscript.

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  1. Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan

    Tomoo Hirano

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Hirano, T. Glutamate-Receptor-Like Molecule GluRδ2 Involved in Synapse Formation at Parallel Fiber-Purkinje Neuron Synapses. Cerebellum 11, 71–77 (2012). https://doi.org/10.1007/s12311-010-0170-0

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