Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

D-Serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor

Nature Neuroscience volume 14, pages 603–611 (2011)Cite this article

Subjects

Abstract

D-Serine (D-Ser) is an endogenous co-agonist for NMDA receptors and regulates neurotransmission and synaptic plasticity in the forebrain. D-Ser is also found in the cerebellum during the early postnatal period. Although D-Ser binds to the δ2 glutamate receptor (GluD2, Grid2) in vitro, its physiological significance has remained unclear. Here we show that D-Ser serves as an endogenous ligand for GluD2 to regulate long-term depression (LTD) at synapses between parallel fibers and Purkinje cells in the immature cerebellum. D-Ser was released mainly from Bergmann glia after the burst stimulation of parallel fibers in immature, but not mature, cerebellum. D-Ser rapidly induced endocytosis of AMPA receptors and mutually occluded LTD in wild-type, but not Grid2-null, Purkinje cells. Moreover, mice expressing mutant GluD2 in which the binding site for D-Ser was disrupted showed impaired LTD and motor dyscoordination during development. These results indicate that glial D-Ser regulates synaptic plasticity and cerebellar functions by interacting with GluD2.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: D-Ser causes a decrease in PF-EPSCs through GluD2.
Figure 2: D-Ser induces AMPA receptor endocytosis by binding to GluD2.
Figure 3: Activity-dependent increase in extracellular [D-Ser] in immature wild-type cerebellar slices.
Figure 4: Endogenous D-Ser is released mainly from Bergmann glia and regulates LTD in the developing cerebellum.
Figure 5: Cerebellar LTD is enhanced by D-Ser binding to GluD2 in the developing cerebellum.
Figure 6: Disruption of D-Ser binding to GluD2 impaired motor coordination and learning in developing mice.
Figure 7: D-Ser conveys signals for LTD through the cytoplasmic C-terminal tails of GluD2 independent of its channel function but dependent on PKC activities in immature Purkinje cells.

Similar content being viewed by others

References

  1. Hashimoto, A. & Oka, T. Free D-aspartate and D-serine in the mammalian brain and periphery. Prog. Neurobiol. 52, 325–353 (1997).

    Article  CAS  Google Scholar 

  2. Oliet, S.H. & Mothet, J.P. Regulation of N-methyl-D-aspartate receptors by astrocytic D-serine. Neuroscience 158, 275–283 (2009).

    Article  CAS  Google Scholar 

  3. Henneberger, C., Papouin, T., Oliet, S.H. & Rusakov, D.A. Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010).

    Article  CAS  Google Scholar 

  4. Billard, J.M. D-Serine signalling as a prominent determinant of neuronal-glial dialogue in the healthy and diseased brain. J. Cell. Mol. Med. 12, 1872–1884 (2008).

    Article  CAS  Google Scholar 

  5. Schell, M.J., Brady, R.O. Jr., Molliver, M.E. & Snyder, S.H. D-Serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J. Neurosci. 17, 1604–1615 (1997).

    Article  CAS  Google Scholar 

  6. Schell, M.J., Molliver, M.E. & Snyder, S.H. D-Serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc. Natl. Acad. Sci. USA 92, 3948–3952 (1995).

    Article  CAS  Google Scholar 

  7. Wang, L.Z. & Zhu, X.Z. Spatiotemporal relationships among D-serine, serine racemase, and D-amino acid oxidase during mouse postnatal development. Acta Pharmacol. Sin. 24, 965–974 (2003).

    CAS  PubMed  Google Scholar 

  8. Kashiwabuchi, N. et al. Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluRδ2 mutant mice. Cell 81, 245–252 (1995).

    Article  CAS  Google Scholar 

  9. Naur, P. et al. Ionotropic glutamate-like receptor δ2 binds D-serine and glycine. Proc. Natl. Acad. Sci. USA 104, 14116–14121 (2007).

    Article  CAS  Google Scholar 

  10. Hansen, K.B. et al. Modulation of the dimer interface at ionotropic glutamate-like receptor δ2 by D-serine and extracellular calcium. J. Neurosci. 29, 907–917 (2009).

    Article  CAS  Google Scholar 

  11. Hirai, H. et al. New role of δ2-glutamate receptors in AMPA receptor trafficking and cerebellar function. Nat. Neurosci. 6, 869–876 (2003).

    Article  CAS  Google Scholar 

  12. Hirai, H. et al. Rescue of abnormal phenotypes of the δ2 glutamate receptor-null mice by mutant δ2 transgenes. EMBO Rep. 6, 90–95 (2005).

    Article  CAS  Google Scholar 

  13. Zucker, R.S. & Regehr, W.G. Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002).

    Article  CAS  Google Scholar 

  14. Casado, M., Isope, P. & Ascher, P. Involvement of presynaptic N-methyl-D-aspartate receptors in cerebellar long-term depression. Neuron 33, 123–130 (2002).

    Article  CAS  Google Scholar 

  15. Shin, J.H. & Linden, D.J. An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. J. Neurophysiol. 94, 4281–4289 (2005).

    Article  CAS  Google Scholar 

  16. Kakegawa, W. et al. The N-terminal domain of GluD2 (GluRδ2) recruits presynaptic terminals and regulates synaptogenesis in the cerebellum in vivo. J. Neurosci. 29, 5738–5748 (2009).

    Article  CAS  Google Scholar 

  17. Matsuda, S., Launey, T., Mikawa, S. & Hirai, H. Disruption of AMPA receptor GluR2 clusters following long-term depression induction in cerebellar Purkinje neurons. EMBO J. 19, 2765–2774 (2000).

    Article  CAS  Google Scholar 

  18. Xia, J., Chung, H.J., Wihler, C., Huganir, R.L. & Linden, D.J. Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron 28, 499–510 (2000).

    Article  CAS  Google Scholar 

  19. Lee, S.H., Liu, L., Wang, Y.T. & Sheng, M. Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron 36, 661–674 (2002).

    Article  CAS  Google Scholar 

  20. Hirai, H. et al. Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat. Neurosci. 8, 1534–1541 (2005).

    Article  CAS  Google Scholar 

  21. Kakegawa, W., Kohda, K. & Yuzaki, M. The δ2 'ionotropic' glutamate receptor functions as a non-ionotropic receptor to control cerebellar synaptic plasticity. J. Physiol. (Lond.) 584, 89–96 (2007).

    Article  CAS  Google Scholar 

  22. Kakegawa, W. et al. Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRδ2. J. Neurosci. 28, 1460–1468 (2008).

    Article  CAS  Google Scholar 

  23. Miyoshi, Y. et al. Determination of D-serine and D-alanine in the tissues and physiological fluids of mice with various D-amino-acid oxidase activities using two-dimensional high-performance liquid chromatography with fluorescence detection. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 877, 2506–2512 (2009).

    Article  CAS  Google Scholar 

  24. Hashimoto, A., Oka, T. & Nishikawa, T. Extracellular concentration of endogenous free D-serine in the rat brain as revealed by in vivo microdialysis. Neuroscience 66, 635–643 (1995).

    Article  CAS  Google Scholar 

  25. Panatier, A. et al. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125, 775–784 (2006).

    Article  CAS  Google Scholar 

  26. Zhang, Z., Gong, N., Wang, W., Xu, L. & Xu, T.L. Bell-shaped D-serine actions on hippocampal long-term depression and spatial memory retrieval. Cereb. Cortex 18, 2391–2401 (2008).

    Article  Google Scholar 

  27. Kim, P.M. et al. Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. Proc. Natl. Acad. Sci. USA 102, 2105–2110 (2005).

    Article  CAS  Google Scholar 

  28. Mothet, J.P. et al. Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine. Proc. Natl. Acad. Sci. USA 102, 5606–5611 (2005).

    Article  CAS  Google Scholar 

  29. Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).

    Article  CAS  Google Scholar 

  30. Wolosker, H., Blackshaw, S. & Snyder, S.H. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc. Natl. Acad. Sci. USA 96, 13409–13414 (1999).

    Article  CAS  Google Scholar 

  31. Miya, K. et al. Serine racemase is predominantly localized in neurons in mouse brain. J. Comp. Neurol. 510, 641–654 (2008).

    Article  CAS  Google Scholar 

  32. Williams, S.M., Diaz, C.M., Macnab, L.T., Sullivan, R.K. & Pow, D.V. Immunocytochemical analysis of D-serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons. Glia 53, 401–411 (2006).

    Article  Google Scholar 

  33. Lev-Ram, V., Jiang, T., Wood, J., Lawrence, D.S. & Tsien, R.Y. Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. Neuron 18, 1025–1038 (1997).

    Article  CAS  Google Scholar 

  34. Yang, Y. et al. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc. Natl. Acad. Sci. USA 100, 15194–15199 (2003).

    Article  CAS  Google Scholar 

  35. Yamamoto, M. et al. Reversible suppression of glutamatergic neurotransmission of cerebellar granule cells in vivo by genetically manipulated expression of tetanus neurotoxin light chain. J. Neurosci. 23, 6759–6767 (2003).

    Article  CAS  Google Scholar 

  36. Tanaka, K. & Augustine, G.J. A positive feedback signal transduction loop determines timing of cerebellar long-term depression. Neuron 59, 608–620 (2008).

    Article  CAS  Google Scholar 

  37. Yuzaki, M. New (but old) molecules regulating synapse integrity and plasticity: Cbln1 and the δ2 glutamate receptor. Neuroscience 162, 633–643 (2009).

    Article  CAS  Google Scholar 

  38. Matsuda, K. et al. Cbln1 is a ligand for an orphan glutamate receptor δ2, a bidirectional synapse organizer. Science 328, 363–368 (2010).

    Article  CAS  Google Scholar 

  39. Tregnago, M., Virgili, M., Monti, B., Guarnieri, T. & Contestabile, A. Alteration of neuronal nitric oxide synthase activity and expression in the cerebellum and the forebrain of microencephalic rats. Brain Res. 793, 54–60 (1998).

    Article  CAS  Google Scholar 

  40. Wang, W., Nakayama, T., Inoue, N. & Kato, T. Quantitative analysis of nitric oxide synthase expressed in developing and differentiating rat cerebellum. Brain Res. Dev. Brain Res. 111, 65–75 (1998).

    Article  CAS  Google Scholar 

  41. Jurado, S., Sanchez-Prieto, J. & Torres, M. Differential expression of NO-sensitive guanylyl cyclase subunits during the development of rat cerebellar granule cells: regulation via N-methyl-D-aspartate receptors. J. Cell Sci. 116, 3165–3175 (2003).

    Article  CAS  Google Scholar 

  42. Lehre, K.P. & Rusakov, D.A. Asymmetry of glia near central synapses favors presynaptically directed glutamate escape. Biophys. J. 83, 125–134 (2002).

    Article  CAS  Google Scholar 

  43. Yao, Y., Harrison, C.B., Freddolino, P.L., Schulten, K. & Mayer, M.L. Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors. EMBO J. 27, 2158–2170 (2008).

    Article  CAS  Google Scholar 

  44. Zafra, F. et al. Glycine transporters are differentially expressed among CNS cells. J. Neurosci. 15, 3952–3969 (1995).

    Article  CAS  Google Scholar 

  45. Nicholson, C., ten Bruggencate, G., Stockle, H. & Steinberg, R. Calcium and potassium changes in extracellular microenvironment of cat cerebellar cortex. J. Neurophysiol. 41, 1026–1039 (1978).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We appreciate Shiseido Co., Ltd. for their technical support concerning the 2D-HPLC analysis of D-Ser. We thank M. Watanabe for the antibodies to GluD2 and 3-PGDH, S. Nakanishi for the GFP-TeNT cDNA, M. Mishina for the Grid2-null mouse, and T. Takahashi, S. Jitsuki and T. Nishikawa for comments. This work was supported by a Grant-in-Aid for the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.Y. and W.K.), Core Research for Evolutional Science and Technology from the Japanese Science and Technology Agency (M.Y.), Keio Gijuku Academic Development Funds (W.K.), the Keio University Medical Science Fund, Research Grants for Life Science and Medicine (W.K.), the Naito Foundation Subsidy for Promotion of Specific Research Projects (W.K.) and the Takeda Science Foundation (M.Y.).

Author information

Authors and Affiliations

  1. Department of Physiology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan

    Wataru Kakegawa, Shinji Matsuda, Keiko Matsuda, Kazuhisa Kohda, Kyoichi Emi, Junko Motohashi & Michisuke Yuzaki

  2. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan.,

    Wataru Kakegawa, Shinji Matsuda, Keiko Matsuda, Kazuhisa Kohda, Kyoichi Emi, Junko Motohashi & Michisuke Yuzaki

  3. Graduate School of Pharmaceutical Science, Kyushu University, Higashi-ku, Fukuoka, Japan

    Yurika Miyoshi, Kenji Hamase & Kiyoshi Zaitsu

  4. Center for Medical Science, International University of Health and Welfare Graduate School, Ohtawara, Tochigi, Japan

    Ryuichi Konno

Authors
  1. Wataru Kakegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yurika Miyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenji Hamase
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shinji Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiko Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuhisa Kohda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kyoichi Emi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junko Motohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ryuichi Konno
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kiyoshi Zaitsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michisuke Yuzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.K. designed the experiments, performed the electrophysiological, immunohistochemical and behavioral studies, analyzed the data, and wrote the manuscript. Y.M., K.H. and K.Z. performed 2D-HPLC analysis. S.M. and K.M. performed cell surface staining. K.K. prepared the recombinant viruses and performed the biochemical analysis. K.E. supported behavioral experiments. J.M. performed biochemical assays and maintained mouse lines. R.K. provided the Dao−/− mouse. M.Y. supervised the project, designed the experiments and wrote the manuscript.

Corresponding author

Correspondence to Michisuke Yuzaki.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–17 (PDF 1043 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kakegawa, W., Miyoshi, Y., Hamase, K. et al. D-Serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor. Nat Neurosci 14, 603–611 (2011). https://doi.org/10.1038/nn.2791

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2791

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing