title: D-serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor.
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.
authors: Department of Physiology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Wataru
authors: W
authors: Kakegawa
authors: Yurika
authors: Y
authors: Miyoshi
authors: Kenji
authors: K
authors: Hamase
authors: Shinji
authors: S
authors: Matsuda
authors: Keiko
authors: K
authors: Matsuda
authors: Kazuhisa
authors: K
authors: Kohda
authors: Kyoichi
authors: K
authors: Emi
authors: Junko
authors: J
authors: Motohashi
authors: Ryuichi
authors: R
authors: Konno
authors: Kiyoshi
authors: K
authors: Zaitsu
authors: Michisuke
authors: M
authors: Yuzaki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics / Q000379:methods; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003605:D-Amino-Acid Oxidase / Q000172:deficiency; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018684:Glycine Agents / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis / Q000379:methods; D009154:Mutation / Q000235:genetics; D018408:Patch-Clamp Techniques; D050543:Phosphoglycerate Dehydrogenase / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000172:deficiency / Q000502:physiology*; D045442:Rotarod Performance Test / Q000379:methods; D012694:Serine / Q000378:metabolism* / Q000494:pharmacology; D018709:Statistics, Nonparametric; D013331:Strychnine / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018684:Glycine Agents; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2; D049452:Green Fluorescent Proteins; D012694:Serine; C056639:2-amino-5-phosphopentanoic acid; D050543:Phosphoglycerate Dehydrogenase; C485958:Dao1 protein, mouse; D003605:D-Amino-Acid Oxidase; D013331:Strychnine; D014633:Valine