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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Animals, Newborn
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Biophysics / methods
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Cells, Cultured
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Cerebellum / cytology*
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Chromatography, High Pressure Liquid / methods
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D-Amino-Acid Oxidase / deficiency
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Electric Stimulation / methods
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Glycine Agents / pharmacology
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Green Fluorescent Proteins / genetics
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Long-Term Synaptic Depression / drug effects
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Long-Term Synaptic Depression / physiology*
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Mice
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Mice, Transgenic
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Microdialysis / methods
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Mutation / genetics
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Patch-Clamp Techniques
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Phosphoglycerate Dehydrogenase / metabolism
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Psychomotor Performance / drug effects
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Psychomotor Performance / physiology*
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Purkinje Cells / drug effects
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Purkinje Cells / physiology
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Receptors, Glutamate / deficiency
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Receptors, Glutamate / physiology*
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Rotarod Performance Test / methods
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Serine / metabolism*
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Serine / pharmacology
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Statistics, Nonparametric
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Strychnine / pharmacology
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Valine / analogs & derivatives
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Valine / pharmacology
Substances
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Excitatory Amino Acid Antagonists
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Glycine Agents
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Receptors, Glutamate
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glutamate receptor delta 2
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Green Fluorescent Proteins
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Serine
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2-amino-5-phosphopentanoic acid
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Phosphoglycerate Dehydrogenase
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Dao1 protein, mouse
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D-Amino-Acid Oxidase
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Strychnine
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Valine