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.
At a glance
- Free D-aspartate and D-serine in the mammalian brain and periphery. Prog. Neurobiol. 52, 325–353 (1997). &
- Regulation of N-methyl-D-aspartate receptors by astrocytic D-serine. Neuroscience 158, 275–283 (2009). &
- Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010). , , &
- 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).
- D-Serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J. Neurosci. 17, 1604–1615 (1997). , , &
- D-Serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc. Natl. Acad. Sci. USA 92, 3948–3952 (1995). , &
- Spatiotemporal relationships among D-serine, serine racemase, and D-amino acid oxidase during mouse postnatal development. Acta Pharmacol. Sin. 24, 965–974 (2003). &
- Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluRδ2 mutant mice. Cell 81, 245–252 (1995). et al.
- Ionotropic glutamate-like receptor δ2 binds D-serine and glycine. Proc. Natl. Acad. Sci. USA 104, 14116–14121 (2007). 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). et al.
- New role of δ2-glutamate receptors in AMPA receptor trafficking and cerebellar function. Nat. Neurosci. 6, 869–876 (2003). et al.
- Rescue of abnormal phenotypes of the δ2 glutamate receptor-null mice by mutant δ2 transgenes. EMBO Rep. 6, 90–95 (2005). et al.
- Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002). &
- Involvement of presynaptic N-methyl-D-aspartate receptors in cerebellar long-term depression. Neuron 33, 123–130 (2002). , &
- 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). &
- The N-terminal domain of GluD2 (GluRδ2) recruits presynaptic terminals and regulates synaptogenesis in the cerebellum in vivo. J. Neurosci. 29, 5738–5748 (2009). et al.
- Disruption of AMPA receptor GluR2 clusters following long-term depression induction in cerebellar Purkinje neurons. EMBO J. 19, 2765–2774 (2000). , , &
- Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron 28, 499–510 (2000). , , , &
- 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). , , &
- Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat. Neurosci. 8, 1534–1541 (2005). et al.
- The δ2 'ionotropic' glutamate receptor functions as a non-ionotropic receptor to control cerebellar synaptic plasticity. J. Physiol. (Lond.) 584, 89–96 (2007). , &
- Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRδ2. J. Neurosci. 28, 1460–1468 (2008). 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). et al.
- Extracellular concentration of endogenous free D-serine in the rat brain as revealed by in vivo microdialysis. Neuroscience 66, 635–643 (1995). , &
- Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125, 775–784 (2006). et al.
- Bell-shaped D-serine actions on hippocampal long-term depression and spatial memory retrieval. Cereb. Cortex 18, 2391–2401 (2008). , , , &
- 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). 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). et al.
- Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001). et al.
- 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). , &
- Serine racemase is predominantly localized in neurons in mouse brain. J. Comp. Neurol. 510, 641–654 (2008). et al.
- Immunocytochemical analysis of D-serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons. Glia 53, 401–411 (2006). , , , &
- Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. Neuron 18, 1025–1038 (1997). , , , &
- Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc. Natl. Acad. Sci. USA 100, 15194–15199 (2003). 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). et al.
- A positive feedback signal transduction loop determines timing of cerebellar long-term depression. Neuron 59, 608–620 (2008). &
- New (but old) molecules regulating synapse integrity and plasticity: Cbln1 and the δ2 glutamate receptor. Neuroscience 162, 633–643 (2009).
- Cbln1 is a ligand for an orphan glutamate receptor δ2, a bidirectional synapse organizer. Science 328, 363–368 (2010). et al.
- Alteration of neuronal nitric oxide synthase activity and expression in the cerebellum and the forebrain of microencephalic rats. Brain Res. 793, 54–60 (1998). , , , &
- Quantitative analysis of nitric oxide synthase expressed in developing and differentiating rat cerebellum. Brain Res. Dev. Brain Res. 111, 65–75 (1998). , , &
- 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). , &
- Asymmetry of glia near central synapses favors presynaptically directed glutamate escape. Biophys. J. 83, 125–134 (2002). &
- Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors. EMBO J. 27, 2158–2170 (2008). , , , &
- Glycine transporters are differentially expressed among CNS cells. J. Neurosci. 15, 3952–3969 (1995). et al.
- Calcium and potassium changes in extracellular microenvironment of cat cerebellar cortex. J. Neurophysiol. 41, 1026–1039 (1978). , , &
- Supplementary Text and Figures (1M)
Supplementary Figures 1–17