Glutamate as a neuron-to-glial signal for mitogenesis: role of glialN-methyl-d-aspartate receptors

Uchihori, Yasutaka; Puro, Donald G.

doi:10.1016/0006-8993(93)90901-x

Cited by 78 publications

(44 citation statements)

References 29 publications

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“…However, NMDA receptors have also been described in Müller cells (43). Thus, D-serine may function as a coagonist at NMDA receptors of neurons and glial cells.…”

Section: Discussionmentioning

confidence: 99%

d -serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors

Stevens

Esguerra

Kim

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

252

235

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A lthough bacteria and many invertebrate species use both Dand L-enantiomers of amino acids for cellular functions, it was generally believed that higher organisms had a more restricted stereospecificity and were confined to the use of L-amino acids. Thus, the D-amino acids detected in vertebrates were generally assumed to come from ingested material or intestinal flora (1). Indeed, the enzyme D-amino acid oxidase (D-AAO), which degrades many D-amino acids, is found in vertebrate tissues, but it was assumed to exist for degrading D-amino acids from external sources. However, in the past decade, it has become clear that some D-amino (6) proposed that D-serine released by glia plays a regulatory role as a necessary coagonist for the glutamate activation of NMDA receptors. Thus, an expanded model for glutamate synapses emerged in which perisynaptic glial processes respond to glutamate released from the presynaptic neuron by releasing D-serine, which, in turn, facilitates the activation of NMDA receptors on the postsynaptic cell. The functional importance of D-serine was further supported by the more recent discovery that the enzyme serine racemase, which converts L-serine to D-serine, is localized to astrocytes in the nervous system (7). The discovery of this mechanism adds to the accumulating evidence that glial cells dynamically influence neuronal activity.Although D-serine and serine racemase have been found in many regions of the brain, no study has yet been carried out in the vertebrate retina, a tissue that offers several advantages for studying the actions of D-serine. The retinal network is a well-characterized region of the central nervous system that can be studied in an intact preparation, permitting the use of light stimulation to provide natural activation of the neural circuitry and test more directly the physiological significance of D-serine. Virtually all retinal ganglion cells have AMPA and NMDA receptors, which both contribute to light-evoked excitation (8-12), and NMDA receptor currents can be enhanced through pharmacological techniques and studied in relative isolation from AMPA receptor contributions (13).In the present study, we have used immunohistochemistry, immunoblotting, analytical chemistry (HPLC), and electrophysiology to evaluate the presence of D-serine and serine racemase in the retinas of several vertebrate species. Our findings indicate that D-serine and serine racemase are present in the retina and seem to be localized to Müller glial cells and astrocytes. In addition, we have demonstrated that exogenous D-serine can enhance NMDA receptor responses and modulate light-evoked activity in retinal ganglion cells. The enhancement of NMDA receptor function seems to involve both tonic and phasic components of glutamatergic input. When the D-serine-degrading enzyme D-AAO (14) is added to the bathing medium, currents mediated by NMDA receptors are reduced, suggesting that these responses depend on endogenous D-serine as a coagonist for the glutamate activation of NMDA receptors. Method...

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“…However, NMDA receptors have also been described in Müller cells (43). Thus, D-serine may function as a coagonist at NMDA receptors of neurons and glial cells.…”

Section: Discussionmentioning

confidence: 99%

d -serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors

Stevens

Esguerra

Kim

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

252

235

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“…Since the Wenthold and NR1-C1 antibodies recognize an overlapping subset of NRl splice variants, it is likely that glial processes in visual cortex express a subset of splice variants (i.e., NR1-2aib and/or NR1-4a/b, but not NR1-la/b and NR1-3a/b). Nonetheless, the functional significance of NMDA receptor expression in glial cells remains unclear (Herrera and Cuello, 1992;Uchihori and Puro, 1993;Kirchhoff et al, 1993;Muller et al, 1993).…”

Section: Glial Expression Ofnrl Splice Variantsmentioning

confidence: 98%

Regional and laminar differences in synaptic localization of NMDA receptor subunit NR1 splice variants in rat visual cortex and hippocampus

1996

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Changes in N-methyl-D-aspartate (NMDA) receptor expression may represent a molecular substrate for differences in synaptic plasticity between early postnatal and adult brains (Fox and Zahs [1994] Curr. Opinion Neurobiol. 4:112-119). We have, therefore, examined the regional and laminar distribution of NR1, the essential subunit of the NMDA receptor, in two regions in which synaptic plasticity has been most thoroughly studied: primary visual cortex and hippocampus. To study NR1 expression at the light and electron microscopic levels we have used a new antiserum (NR1-C1; Sheng et al. [1994] Nature 368:144-147) directed against a differentially spliced C-terminal exon ("C1"). The most striking result was that the pattern of NR1-C1 labeling in the adult was more restricted than that of previously published NR1-specific antibodies. Specifically, NR1-C1 did not label cells in the CA3, dentate gyrus or subicular regions of the hippocampus or in layer 4 of the visual cortex. Quantitative ultrastructural analysis revealed that these differences were paralleled by differential expression of NR1-C1 at synapses. In sharp contrast to the pattern in the adult, NR1-C1 immunoreactivity was distributed more widely in the developing brain. At postnatal day 11, NR1-C1 splice variants were expressed in all layers of the visual cortex and in all regions of the hippocampus. The transient expression of NR1-C1 splice variants in layer 4 of visual cortex suggests that NR1-C1 may play a role in determining the critical period for binocular plasticity. Continued expression of NR1-C1 in upper and lower layers of the adult cortex and in CA1 of the hippocampus may provide a substrate for plasticity in corticocortical connections and Schaffer collateral synapses beyond the critical period. In addition to abundant postsynaptic staining, NR1-C1 immunoreactivity was found in a large number of axon terminals in the dorsal subiculum, but in very few terminals in visual cortex. This strongly suggests that presynaptic NMDA receptors play a major role in neuronal processing of hippocampal output through the subiculum, but play a relatively minor role in visual processing.

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“…NMDA-R1-li immunoreactivity was also localized to plasmalemmal sites on astrocytes that were in contact with TH-labeled dendrites. This astrocytic labeling may reflect sites where glutamate acts at NMDA receptors to mediate slow chemical and metabolic changes in glial fibrillary acidic protein (Herrera and Cuello, 1992) and changes in astrocytic proliferation (Uchicori and Puro, 1993). This may be particularly important for the LC especially during development.…”

Section: Subcellular Localization Of the Nmda-r1-li Receptor In Astromentioning

confidence: 98%

Selective distribution of the NMDA-R1 glutamate receptor in astrocytes and presynaptic axon terminals in the nucleus locus coeruleus of the rat brain: An immunoelectron microscopic study

Bockstaele

Colago

1996

J. Comp. Neurol.

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The regional and cellular distribution of the different classes of excitatory amino acid receptors with respect to the noradrenergic neurons of the nucleus locus coeruleus (LC) are unknown. We therefore combined immunoperoxidase labeling for the R1 subunit of the N-methy-D-aspartate (NMDA) receptor with immunogold-silver localization of the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), in single sections through the rat LC to determine the subcellular localization of this glutamate receptor subtype with respect to the noradrenergic neurons. At the light microscopic level, there was light to moderate labeling for the NMDA-R1-like (li) receptor in the caudal pole of the LC and dense labeling in the dorsolateral aspect of the LC adjacent to the superior cerebellar peduncle. In the rostral pole of the LC which is enriched with noradrenergic dendrites, significant overlap between both immunoreactivities could be observed. At the ultrastructural level, immunoperoxidase labeling for NMDA-R1 was selectively distributed in astrocytic processes and within presynaptic axon terminals but was rarely seen in catecholamine-containing somata or dendrites. Peroxidase labeling for NMDA-R1, however, was occasionally observed in dendrites in the rostral pole of the LC. Most of these dendrites lacked detectable levels of TH, although TH immunoreactivity was apparent in the neuropil. Dendrites containing NMDA-R1-li immunoreactivity often received asymmetric (excitatory-type) contacts from unlabeled terminals. NMDA-R1-li-immunoreactive axon terminals usually contained small clear, as well as large dense-core vesicles and were often apposed to unlabeled dendrites, axon terminals and/or glial processes. These results provide the first ultrastructural evidence that NMDA-R1-li immunoreactivity is selectively distributed within astrocytic processes and presynaptic axon terminals within the LC.

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Glutamate as a neuron-to-glial signal for mitogenesis: role of glialN-methyl-d-aspartate receptors

Cited by 78 publications

References 29 publications

d -serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors

d -serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors

Regional and laminar differences in synaptic localization of NMDA receptor subunit NR1 splice variants in rat visual cortex and hippocampus

Selective distribution of the NMDA-R1 glutamate receptor in astrocytes and presynaptic axon terminals in the nucleus locus coeruleus of the rat brain: An immunoelectron microscopic study

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