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

Wataru Kakegawa, Yurika Miyoshi, Kenji Hamase, Shinji Matsuda, Keiko Matsuda, Kazuhisa Kohda, Kyoichi Emi, Junko Motohashi, Ryuichi Konno, Kiyoshi Zaitsu, Michisuke Yuzaki

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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 δ 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.

Original languageEnglish
Pages (from-to)603-613
Number of pages11
JournalNature Neuroscience
Issue number5
Publication statusPublished - 2011 May 1


ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Kakegawa, W., Miyoshi, Y., Hamase, K., Matsuda, S., Matsuda, K., Kohda, K., Emi, K., Motohashi, J., Konno, R., Zaitsu, K., & Yuzaki, M. (2011). D-Serine regulates cerebellar LTD and motor coordination through the δ glutamate receptor. Nature Neuroscience, 14(5), 603-613. https://doi.org/10.1038/nn.2791