The NMDA receptor is a key player in excitatory transmission and synaptic plasticity in the central nervous system. Its activation requires the binding of both glutamate and a co-agonist like D-serine to its glycine site. As D-serine is released exclusively by astrocytes, we studied the physiological impact of the glial environment on NMDA receptor-dependent activity and plasticity. To this end, we took advantage of the changing astrocytic ensheathing of neurons occurring in the supraoptic nucleus during lactation. We provide direct evidence that in this hypothalamic structure the endogenous co-agonist of NMDA receptors is D-serine and not glycine. Consequently, the degree of astrocytic coverage of neurons governs the level of glycine site occupancy on the NMDA receptor, thereby affecting their availability for activation and thus the activity dependence of long-term synaptic changes. Such a contribution of astrocytes to synaptic metaplasticity fuels the emerging concept that astrocytes are dynamic partners of brain signaling.
Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although D-serine is a more potent agonist. Localizations of D-serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely than glycine. We now show that selective degradation of D-serine with D-amino acid oxidase greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMDA receptor-mediated calcium flux. The inhibitory effects of the enzyme are fully reversed by exogenously applied D-serine, which by itself did not potentiate NMDA receptormediated synaptic responses. Thus, D-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses. D-Amino acids play prominent roles in bacteria but have not been thought to occur in substantial quantity or to have any important function in vertebrates. Recently, techniques to distinguish isomers of amino acids in routine assays have led to the identification in some mammalian tissues of substantial amounts of at least two D-amino acids, D-serine and D-aspartate (1). Although D-aspartate is present in selected neuronal populations in the brain, it is concentrated mainly in glands, especially the epinephrine-containing cells of the adrenal medulla, the posterior pituitary, and the pineal gland (2-4).In contrast, D-serine occurs primarily in the brain, with highest concentrations in regions enriched in N-methyl-D-aspartate (NMDA) receptors (5-7). In these areas immunohistochemical studies have localized D-serine to protoplasmic astrocytes, which ensheathe nerve terminals especially in areas of the brain enriched in NMDA receptors (7). Stimulation of the kainate subtype of glutamate receptor releases D-serine from protoplasmic astrocytes (7).Because exogenous D-serine potentiates NMDA receptormediated neurotransmission (8-11) and D-[ 3 H]serine selectively binds to the glycine site (6), D-serine has been proposed as an endogenous ligand for the strychnine-insensitive glycine site of the NMDA receptor (6). Activation of NMDA receptors requires the presence of a coagonist, initially thought to be glycine (8,(12)(13)(14), and a glycine-selective recognition domain has been localized on NMDA receptors (15-17). However, D-serine is at least as potent as glycine as a coagonist at this site (8,10,14). In addition, immunohistochemical studies have revealed an overlapping distribution of D-serine and NMDA receptor immunoreactivity in forebrain (7). In the developing cerebellum, D-serine is localized to Bergmann glia that regulate granule cell migration during development via NMDA receptors (7). In contrast, glycine immunoreactivity is localized differently from that of NMDA receptors except in the brainstem, where it closely parallels the distribution of NMDA receptors (7). Extracell...
N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, d-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for d-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and d-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology.
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