Journal articles: 'Glutamate transporter GLAST'

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Chen, Zhiqiang, Sharon G. Kujawa, and William F. Sewell. "Functional Roles of High-Affinity Glutamate Transporters in Cochlear Afferent Synaptic Transmission in the Mouse." Journal of Neurophysiology 103, no. 5 (May 2010): 2581–86. http://dx.doi.org/10.1152/jn.00018.2010.

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In the cochlea, afferent transmission between inner hair cells and auditory neurons is mediated by glutamate receptors. Glutamate transporters located near the synapse and in spiral ganglion neurons are thought to maintain low synaptic levels of glutamate. We analyzed three glutamate transporter blockers for their ability to alter the effects of glutamate, exogenously applied to the synapse via perfusion of the scala tympani of the mouse, and compared that action to their ability to alter the effects of intense acoustic stimulation. Threo-beta-benzyloxyaspartate (TBOA) is a broad-spectrum glutamate transporter antagonist, affecting all three transporters [glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT1), and excitatory amino acid carrier 1 (EAAC1)]. l-serine- O-sulfate (SOS) blocks both GLAST and EAAC1 without effect on GLT1. Dihydrokainate (DHK) is selective for GLT1. Infusion of glutamate (10 μM for 220 min), TBOA (200 μM for 220 min), or SOS (100 μM for 180 min) alone did not alter auditory neural thresholds. When infused together with glutamate, TBOA and SOS produced significant neural threshold shifts, leaving otoacoustic emissions intact. In addition, both TBOA and SOS exacerbated noise-induced hearing loss by producing larger neural threshold shifts and delaying recovery. DHK did not alter glutamate- or noise-induced hearing loss. The evidence points to a major role for GLAST, both in protecting the synapse from exposure to excess extracellular glutamate and in attenuating hearing loss due to acoustic overstimulation.

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SARTHY, VIJAY P., V. JOSEPH DUDLEY, and KOHICHI TANAKA. "Retinal glucose metabolism in mice lacking the L-glutamate/aspartate transporter." Visual Neuroscience 21, no. 4 (July 2004): 637–43. http://dx.doi.org/10.1017/s0952523804214122.

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The conventional view that glucose is the substrate for neuronal energy metabolism has been recently challenged by the “lactate shuttle” hypothesis in which glutamate cycling in glial cells drives all neuronal glucose metabolism. According to this view, glutamate released by activated retinal neurons is transported into Müller (glial) cells where it triggers glycolysis. The lactate released by Müller cells serves as the energy substrate for neuronal metabolism. Because the L-Glutamate/aspartate transporter (GLAST) is the predominant, Na+-dependent, glutamate transporter expressed by Müller cells, we have used GLAST-knockout (GLAST−/−) mice to examine the relationship between lactate release and GLAST activity in the retina. We found that glucose uptake and lactate production by the GLAST−/− mouse retina was similar to that observed in the wild type mouse retina. Furthermore, addition of 1 mM glutamate and NH4Cl to the incubation medium did not further stimulate glucose uptake in either case. When lactate release was measured in the presence of the lactate uptake inhibitor, α-cyano-4-hydroxycinnamate, there was no significant change in the amount of lactate released by retinas from GLAST−/− mice compared to the wild type. Finally, lactate release was similar under both dark and light conditions. These results show that lactate production and release is not altered in retinas of GLAST−/− mice, which suggests that metabolic coupling between photoreceptors and Müller cells is not mediated by the glial glutamate transporter, GLAST.

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Fujita, Hiroko, Kohji Sato, Tong-Chun Wen, Yi Peng, and Masahiro Sakanaka. "Differential Expressions of Glycine Transporter 1 and Three Glutamate Transporter mRNA in the Hippocampus of Gerbils with Transient Forebrain Ischemia." Journal of Cerebral Blood Flow & Metabolism 19, no. 6 (June 1999): 604–15. http://dx.doi.org/10.1097/00004647-199906000-00003.

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The extracellular concentrations of glutamate and its co-agonist for the N-methyl-d-aspartate (NMDA) receptor, glycine, may be under the control of amino acid transporters in the ischemic brain, However, there is little information on changes in glycine and glutamate transporters in the hippocampal CA1 field of gerbils with transient forebrain ischemia. This study investigated the spatial and temporal expressions of glycine transporter 1 (GLYT 1) and three glutamate transporter (excitatory amino acid carrier 1, EAAC 1; glutamate/aspartate transporter, GLAST; glutamate transporter 1, GLT1) mRNA in the gerbil hippocampus after 3 minutes of ischemia. The GLYT1 mRNA was transiently upregulated by the second day after ischemia in astrocytelike cells in close vicinity to hippocampal CA1 pyramidal neurons, possibly to reduce glycine concentration in the local extracellular spaces. The EAAC1 mRNA was abundantly expressed in almost all pyramidal neurons and dentate granule cells in the control gerbil hippocampus, whereas the expression level in CA1 pyramidal neurons started to decrease by the fourth day after ischemia in synchrony with degeneration of the CA1 neurons. The GLAST and GLT1 mRNA were rather intensely expressed in the dentate gyrus and CA3 field of the control hippocampus, respectively, but they were weakly expressed in the CA1 field before and after ischemia. As GLAST and GLT1 play a major role in the control of extracellular glutamate concentration, the paucity of these transporters in the CA1 field may account for the vulnerability of CA1 neurons to ischemia, provided that the functional GLAST and GLT1 proteins are also less in the CA1 field than in the CA3 field. This study suggests that the amino acid transporters play pivotal roles in the process of delayed neuronal death in the hippocampal CA1 field.

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Hernández-Melchor, Dinorah, Leticia Ramírez-Martínez, Luis Cid, Cecilia Palafox-Gómez, Esther López-Bayghen, and Arturo Ortega. "EAAT1-dependent slc1a3 Transcriptional Control depends on the Substrate Translocation Process." ASN Neuro 14 (January 2022): 175909142211165. http://dx.doi.org/10.1177/17590914221116574.

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Glutamate, the major excitatory neurotransmitter in the vertebrate brain, is removed from the synaptic cleft by a family of sodium-dependent transporters expressed in neurons and glial cells. The bulk of glutamate uptake activity occurs in glial cells through the sodium-dependent glutamate/aspartate transporter (EAAT1/GLAST) and glutamate transporter 1 (EAAT2/GLT-1). EAAT1/GLAST is the predominant transporter within the cerebellum. It is highly enriched in Bergmann glial cells that span the cerebellar cortex and wrap the most abundant glutamatergic synapses in the central nervous system, the synapse formed by the parallel fibers and the Purkinje cells. In the past years, it has become evident that Bergmann glial cells are involved in glutamatergic transmission. Glutamate transporters are tightly regulated due to their essential role in tripartite synapses. Glutamate regulates EAAT1/GLAST function and gene expression in a receptor-dependent and receptor-independent manner. Through the use of the non-metabolizable EAAT1/GLAST ligand, D-Aspartate, and the well-established chick cerebellar Bergmann glia primary culture, in this contribution, we demonstrate that EAAT1/GLAST down-regulates its expression and function at the transcriptional level through the activation of a signaling pathway that includes the phosphatidyl inositol 3 kinase (PI3K), the Ca2+/diacylglycerol dependent protein kinase PKC and the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). These results favor the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells. Summary statement EAAT1/GLAST down-regulates its expression and function at the transcriptional level by activating a signaling pathway that includes PI3K, PKC and NF-κB, favoring the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells.

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TAMAHARA, Satoshi, Mutsumi INABA, Kota SATO, Naoaki MATSUKI, Yoshiaki HIKASA, and Ken-ichiro ONO. "Non-essential roles of cysteine residues in functional expression and redox regulatory pathways for canine glutamate/aspartate transporter based on mutagenic analysis." Biochemical Journal 367, no. 1 (October 1, 2002): 107–11. http://dx.doi.org/10.1042/bj20011843.

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A redox regulatory mechanism and a molecular link between oxidative and excitotoxic neurodegeneration have been postulated for high-affinity Na+-dependent glutamate transporters. In the present study, mutations were introduced at three cysteine residues in canine glutamate/aspartate transporter (GLAST) to investigate the functional significance of thiol groups in response to oxidation. Cys(-) GLAST, in which all cysteines were replaced by other amino acids, as well as other mutants with disruption of one of three cysteine residues, showed insoluble oligomer formation, which was considered to be due to spontaneous and excessive oxidation as observed in wild-type GLAST. The mutant transporters also showed plasma-membrane localization and glutamate-transport kinetics that were very similar to those of wild-type GLAST. Glutamate-transport activities in COS-7 cells transfected with wild-type and Cys(-) GLAST were inhibited to the same degree when cells were exposed to Hg2+ and were recovered by the addition of thiol-specific reductant dithiothreitol. These findings suggest that cysteine residues are not critical in functional expression of GLAST and the redox-sensing pathway via glutamate transporters.

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Deng, Yu, Zhao-Fa Xu, Wei Liu, Bin Xu, Hai-Bo Yang, and Yan-Gang Wei. "Riluzole-Triggered GSH Synthesis via Activation of Glutamate Transporters to Antagonize Methylmercury-Induced Oxidative Stress in Rat Cerebral Cortex." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/534705.

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Objective. This study was to evaluate the effect of riluzole on methylmercury- (MeHg-) induced oxidative stress, through promotion of glutathione (GSH) synthesis by activating of glutamate transporters (GluTs) in rat cerebral cortex.Methods. Eighty rats were randomly assigned to four groups, control group, riluzole alone group, MeHg alone group, and riluzole + MeHg group. The neurotoxicity of MeHg was observed by measuring mercury (Hg) absorption, pathological changes, and cell apoptosis of cortex. Oxidative stress was evaluated via determining reactive oxygen species (ROS), 8-hydroxy-2-deoxyguanosine (8-OHdG), malondialdehyde (MDAs), carbonyl, sulfydryl, and GSH in cortex. Glutamate (Glu) transport was studied by measuring Glu, glutamine (Gln), mRNA, and protein of glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1).Result. (1) MeHg induced Hg accumulation, pathological injury, and apoptosis of cortex; (2) MeHg increased ROS, 8-OHdG, MDA, and carbonyl, and inhibited sulfydryl and GSH; (3) MeHg elevated Glu, decreased Gln, and downregulated GLAST and GLT-1 mRNA expression and protein levels; (4) riluzole antagonized MeHg-induced downregulation of GLAST and GLT-1 function and expression, GSH depletion, oxidative stress, pathological injury, and apoptosis obviously.Conclusion. Data indicate that MeHg administration induced oxidative stress in cortex and that riluzole could antagonize this situation through elevation of GSH synthesis by activating of GluTs.

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Huggett, J. F., A. Mustafa, L. O'Neal, and D. J. Mason. "The glutamate transporter GLAST-I (EAAT-I) is expressed in the plasma membrane of osteocytes and is responsive to extracellular glutamate concentration." Biochemical Society Transactions 30, no. 6 (November 1, 2002): 890–93. http://dx.doi.org/10.1042/bst0300890.

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The glutamate/aspartate transporter GLAST-1 is expressed in bone in vivo and also exists as a splice variant (GLAST-1a) in which exon 3 is excluded. Since GLAST-1 expression is regulated in bone in response to osteogenic mechanical stimuli in vivo and binding of glutamate to receptors on osteoblasts increases osteoblast number and activity in vitro, control of extracellular glutamate concentrations may be critical for balanced bone remodelling. To determine whether GLAST isoforms may act to regulate extracellular glutamate concentration in bone we investigated whether their pattern or level of expression is responsive to glutamate concentration in bone cells. GLAST-1a mRNA is expressed at lower levels than GLAST-1 mRNA in all cells examined. The GLAST-1a/GLAST-1 mRNA ratio is greater in MLO-Y4 osteocytes than in SaOS-2 osteoblast-like cells, although this does vary in SaOS-2 cells in response to extracellular glutamate concentration. Transfection of MLO-Y4 cells with green fluorescent protein (GFP)-tagged GLAST isoforms revealed a plasma membrane localization of GLAST-1, consistent with its transporter function, whereas GLAST-1a appeared to be expressed within internal vesicles. Interestingly, low extracellular glutamate concentrations redistributed GLAST-1-GFP into a similar internal expression pattern. Regulation of the expression and distribution of GLAST-1 by extracellular glutamate in bone cells indicates that it may regulate glutamate signalling in bone, consistent with its operation in the central nervous system.

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Piao, Chun-Shu, Ashley L. Holloway, Sue Hong-Routson, and Mark S. Wainwright. "Depression following traumatic brain injury in mice is associated with down-regulation of hippocampal astrocyte glutamate transporters by thrombin." Journal of Cerebral Blood Flow & Metabolism 39, no. 1 (November 14, 2017): 58–73. http://dx.doi.org/10.1177/0271678x17742792.

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Depression after traumatic brain injury (TBI) is common but the mechanisms by which TBI causes depression are unknown. TBI decreases glutamate transporters GLT-1 and GLAST and allows extravasation of thrombin. We examined the effects of thrombin on transporter expression in primary hippocampal astrocytes. Application of a PAR-1 agonist caused down-regulation of GLT-1, which was prevented by inhibition of Rho kinase (ROCK). To confirm these mechanisms in vivo, we subjected mice to closed-skull TBI. Thrombin activity in the hippocampus increased one day following TBI. Seven days following TBI, expression of GLT-1 and GLAST was reduced in the hippocampus, and this was prevented by administration of the PAR-1 antagonist SCH79797. Inhibition of ROCK attenuated the decrease in GLT-1, but not GLAST, after TBI. We measured changes in glutamate levels in the hippocampus seven days after TBI using an implanted biosensor. Stress-induced glutamate levels were significantly increased following TBI and this was attenuated by treatment with the ROCK inhibitor fasudil. We quantified depressive behavior following TBI and found that inhibition of PAR-1 or ROCK decreased these behaviors. These results identify a novel mechanism by which TBI results in down-regulation of astrocyte glutamate transporters and implicate astrocyte and glutamate transporter dysfunction in depression following TBI.

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Moshrefi-Ravasdjani, Behrouz, Daniel Ziemens, Nils Pape, Marcel Färfers, and Christine Rose. "Action Potential Firing Induces Sodium Transients in Macroglial Cells of the Mouse Corpus Callosum." Neuroglia 1, no. 1 (July 3, 2018): 106–25. http://dx.doi.org/10.3390/neuroglia1010009.

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Recent work has established that glutamatergic synaptic activity induces transient sodium elevations in grey matter astrocytes by stimulating glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST). Glial sodium transients have diverse functional consequences but are largely unexplored in white matter. Here, we employed ratiometric imaging to analyse sodium signalling in macroglial cells of mouse corpus callosum. Electrical stimulation resulted in robust sodium transients in astrocytes, oligodendrocytes and NG2 glia, which were blocked by tetrodotoxin, demonstrating their dependence on axonal action potentials (APs). Action potential-induced sodium increases were strongly reduced by combined inhibition of ionotropic glutamate receptors and glutamate transporters, indicating that they are related to release of glutamate. While AMPA receptors were involved in sodium influx into all cell types, oligodendrocytes and NG2 glia showed an additional contribution of NMDA receptors. The transporter subtypes GLT-1 and GLAST were detected at the protein level and contributed to glutamate-induced glial sodium signals, indicating that both are functionally relevant for glutamate clearance in corpus callosum. In summary, our results demonstrate that white matter macroglial cells experience sodium influx through ionotropic glutamate receptors and glutamate uptake upon AP generation. Activity-induced glial sodium signalling may thus contribute to the communication between active axons and macroglial cells.

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Miyazaki, Taisuke, Miwako Yamasaki, Kouichi Hashimoto, Kazuhisa Kohda, Michisuke Yuzaki, Keiko Shimamoto, Kohichi Tanaka, Masanobu Kano, and Masahiko Watanabe. "Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells." Proceedings of the National Academy of Sciences 114, no. 28 (June 27, 2017): 7438–43. http://dx.doi.org/10.1073/pnas.1617330114.

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Astrocytes regulate synaptic transmission through controlling neurotransmitter concentrations around synapses. Little is known, however, about their roles in neural circuit development. Here we report that Bergmann glia (BG), specialized cerebellar astrocytes that thoroughly enwrap Purkinje cells (PCs), are essential for synaptic organization in PCs through the action of the l-glutamate/l-aspartate transporter (GLAST). In GLAST-knockout mice, dendritic innervation by the main ascending climbing fiber (CF) branch was significantly weakened, whereas the transverse branch, which is thin and nonsynaptogenic in control mice, was transformed into thick and synaptogenic branches. Both types of CF branches frequently produced aberrant wiring to proximal and distal dendrites, causing multiple CF–PC innervation. Our electrophysiological analysis revealed that slow and small CF-evoked excitatory postsynaptic currents (EPSCs) were recorded from almost all PCs in GLAST-knockout mice. These atypical CF-EPSCs were far more numerous and had significantly faster 10–90% rise time than those elicited by glutamate spillover under pharmacological blockade of glial glutamate transporters. Innervation by parallel fibers (PFs) was also affected. PF synapses were robustly increased in the entire dendritic trees, leading to impaired segregation of CF and PF territories. Furthermore, lamellate BG processes were retracted from PC dendrites and synapses, leading to the exposure of these neuronal elements to the extracellular milieus. These synaptic and glial phenotypes were reproduced in wild-type mice after functional blockade of glial glutamate transporters. These findings highlight that glutamate transporter function by GLAST on BG plays important roles in development and maintenance of proper synaptic wiring and wrapping in PCs.

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Schreiner, Alexandra E., Eric Berlinger, Julia Langer, Karl W. Kafitz, and Christine R. Rose. "Lesion-Induced Alterations in Astrocyte Glutamate Transporter Expression and Function in the Hippocampus." ISRN Neurology 2013 (September 3, 2013): 1–16. http://dx.doi.org/10.1155/2013/893605.

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Astrocytes express the sodium-dependent glutamate transporters GLAST and GLT-1, which are critical to maintain low extracellular glutamate concentrations. Here, we analyzed changes in their expression and function following a mechanical lesion in the CA1 area of organotypic hippocampal slices. 6-7 days after lesion, a glial scar had formed along the injury site, containing strongly activated astrocytes with increased GFAP and S100β immunoreactivity, enlarged somata, and reduced capability for uptake of SR101. Astrocytes in the scar’s periphery were swollen as well, but showed only moderate upregulation of GFAP and S100β and efficiently took up SR101. In the scar, clusters of GLT-1 and GLAST immunoreactivity colocalized with GFAP-positive fibers. Apart from these, GLT-1 immunoreactivity declined with increasing distance from the scar, whereas GLAST expression appeared largely uniform. Sodium imaging in reactive astrocytes indicated that glutamate uptake was strongly reduced in the scar but maintained in the periphery. Our results thus show that moderately reactive astrocytes in the lesion periphery maintain overall glutamate transporter expression and function. Strongly reactive astrocytes in the scar, however, display clusters of GLAST and GLT-1 immunoreactivity together with reduced glutamate transport activity. This reduction might contribute to increased extracellular glutamate concentrations and promote excitotoxic cell damage at the lesion site.

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Suzuki, Keiko, Yuji Ikegaya, Sigeru Matsuura, Yoshikatsu Kanai, Hitoshi Endou, and Norio Matsuki. "Transient upregulation of the glial glutamate transporter GLAST in response to fibroblast growth factor, insulin-like growth factor and epidermal growth factor in cultured astrocytes." Journal of Cell Science 114, no. 20 (October 15, 2001): 3717–25. http://dx.doi.org/10.1242/jcs.114.20.3717.

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Although expression of the glial glutamate transporter GLAST is tightly regulated during development and under pathophysiological conditions, little is known about endogenous modulators of GLAST expression. Because growth factors are generally believed to regulate glial functions, we addressed their possible contribution to GLAST regulation in cultured rat astrocytes. Of the six growth factors tested (basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), insulin, platelet-derived growth factor, and hepatocyte growth factor), bFGF, IGF-1 and EGF enhanced [3H]glutamate transport activity in a concentration-dependent manner. These effects were accompanied by an increase in the Vmax value for transport activity and in GLAST protein and mRNA levels, which suggests that GLAST expression is transcriptionally regulated by the growth factors. Interestingly, the effects reached a peak after 36 hours of exposure to growth factors, and rapidly returned to baseline by 48 hours. A combination of IGF-1 with either bFGF or EGF showed an additive effect on the glutamate uptake activity, but a combination of bFGF and EGF did not. Pharmacological blockade of protein kinase C inhibited the effects of IGF-1 and EGF, but not bFGF. By contrast, genistein, an inhibitor of tyrosine kinases, blocked the effects of bFGF and EGF without affecting the effect of IGF-1. These results suggest that the growth factors activate different signaling pathways for GLAST upregulation. The present study may indicate a novel regulatory system of glial glutamate transporters.

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Gegelashvili, Georgi, Gianluca Civenni, Giorgio Racagni, Niels C. Danbolt, Inger Schousboe, and Arne Schousboe. "Glutamate receptor agonists up-regulate glutamate transporter GLAST in astrocytes." NeuroReport 8, no. 1 (December 1996): 261–65. http://dx.doi.org/10.1097/00001756-199612200-00052.

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Kim, Ha-Neui, Yu-Ri Kim, Ji-Yeon Jang, Hwa-Kyoung Shin, and Byung-Tae Choi. "Electroacupuncture Confers Antinociceptive Effects via Inhibition of Glutamate Transporter Downregulation in Complete Freund's Adjuvant-Injected Rats." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/643973.

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When we evaluated changes of glial fibrillary acidic protein (GFAP) and two glutamate transporter (GTs) by immunohistochemistry, expression of GFAP showed a significant increase in complete Freund's adjuvant (CFA)-injected rats; however, this expression was strongly inhibited by electroacupuncture (EA) stimulation. Robust downregulation of glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) was observed in CFA-injected rats; however, EA stimulation resulted in recovery of this expression. Double-labeling staining showed co-localization of a large proportion of GLAST or GLT-1 with GFAP. Using Western blot, we confirmed protein expression of two GTs, but no differences in the mRNA content of these GTs were observed. Because EA treatment resulted in strong inhibition of CFA-induced proteasome activities, we examined the question of whether thermal sensitivities and GTs expression could be regulated by proteasome inhibitor MG132. CFA-injected rats co-treated with EA and MG132 showed a significantly longer thermal sensitivity, compared with CFA-injected rats with or without MG132. Both EA and MG132 blocked CFA-induced GLAST and GLT-1 downregulation within the spinal cord. These results provide evidence for involvement of GLAST and GLT-1 in response to activation of spinal astrocytes in an EA antinociceptive effect. Antinociceptive effect of EA may be induced via proteasome-mediated regulation of spinal GTs.

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Gonome, Takayuki, Yuting Xie, Saeko Arai, Kodai Yamauchi, Natsuki Maeda-Monai, Reiko Tanabu, Takashi Kudo, and Mitsuru Nakazawa. "Excess Glutamate May Cause Dilation of Retinal Blood Vessels in Glutamate/Aspartate Transporter-Deficient Mice." BioMed Research International 2019 (November 11, 2019): 1–11. http://dx.doi.org/10.1155/2019/6512195.

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Purpose. To investigate the longitudinal findings of fundus features and spectral-domain optical coherence tomography (SD-OCT) to characterize the morphologic features in a mouse model of defective glutamate/aspartate transporter (GLAST−/− mice). Materials and Methods. The fundus findings and SD-OCT images were longitudinally recorded at five time points from postnatal (P) 22 to P156 in GLAST−/− mice. As a control wild type, age-matched C57BL/6J mice were employed. The mouse retina was subdivided into five layers, and the thickness of each layer was longitudinally measured by InSight® using SD-OCT pictures. The SD-OCT findings were compared with the histologic appearances. The diameter of the retinal blood vessels was measured by the ImageJ® software program using SD-OCT images. The data were statistically compared between both age-matched mouse groups. Results. The retinal blood vessels appeared more dilated in GLAST−/− mice than in wild-type mice. This tendency was statistically significant at all time points after P44 by analyses using SD-OCT images. The ganglion cell complex (GCC) and outer nuclear layer (ONL) were significantly thinner in GLAST−/− mice at all time points after P80 than in the wild-type mice. This tendency was more clearly indicated by SD-OCT than histologic sections. Discussion. In the present study, we found for the first time the dilation of the retinal blood vessels and the thinning of the ONL in GLAST−/− mice, in addition to the thinning of the GCC.

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Potapenko, Evgeniy S., Vinicia C. Biancardi, Yiqiang Zhou, and Javier E. Stern. "Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 3 (August 1, 2012): R291—R300. http://dx.doi.org/10.1152/ajpregu.00056.2012.

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Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 μM dihydrokainate (DHK)], resulted in a persistent N-methyl-d-aspartate receptor (NMDAR)-mediated inward current (tonic INMDA) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 μM TBOA) evoked an enhanced tonic INMDA activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.

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Tsuru, Noriko, Yuto Ueda, and Taku Doi. "Amygdaloid Kindling in Glutamate Transporter (GLAST) Knockout Mice." Epilepsia 43, no. 8 (August 2002): 805–11. http://dx.doi.org/10.1046/j.1528-1157.2002.36601.x.

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WANG, ZHIQING, WEI LI, CHERYL K. MITCHELL, and LOUVENIA CARTER-DAWSON. "Activation of protein kinase C reduces GLAST in the plasma membrane of rat Müller cells in primary culture." Visual Neuroscience 20, no. 6 (November 2003): 611–19. http://dx.doi.org/10.1017/s0952523803206039.

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In this study, a Müller cell culture preparation from young rats was used to investigate the regulation of GLAST transport activity in native cells. Immunohistochemical analysis confirmed GLAST to be the predominant glutamate transporter expressed by the cells through five passages. [3H]-glutamate uptake assays showed the typical Na+-dependent glutamate transport which was blocked by L-(-)-threo-3-hydroxyaspartate (L-THA), a competitive inhibitor. Glutamate transport was decreased significantly in Müller cells exposed to phorbol-12-myristate-13-acetate (PMA), a protein kinase C (PKC) activator. A similar effect on [3H]-D-aspartate (nonmetabolizable glutamate analog) uptake ruled out the possibility that the decrease was a consequence of altered metabolism. However, PMA did not affect Na+-dependent [3H]-glycine transport, indicating the absence of a nonspecific change in the electrochemical gradients. The PMA effect on glutamate uptake was evidenced by partial blocking with a specific PKC inhibitor, bisindolymaleimide II (Bis II). Activation of PKC did not change the Km, but the Vmax was significantly reduced. Image analysis of Müller cells with biotinylated cell membranes immunolabeled with GLAST shows a reduction of GLAST in the plasma membrane. In conclusion, these data show that rat Müller cells in primary cultures express GLAST and that PKC activation affects GLAST transport activity by decreasing cell surface expression.

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Lin, Chia-Ho, Han-Yu Chen, and Kai-Che Wei. "Role of HMGB1/TLR4 Axis in Ischemia/Reperfusion-Impaired Extracellular Glutamate Clearance in Primary Astrocytes." Cells 9, no. 12 (December 3, 2020): 2585. http://dx.doi.org/10.3390/cells9122585.

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(1) Background: Abnormal accumulation of extracellular glutamate can occur as dysfunction of astrocytic glutamate transporters, which has been linked to ischemic brain injury. Excessive extracellular glutamate-induced abnormal excitotoxicity is the major cause of secondary neuronal damage after cerebral ischemia/reperfusion. However, the definite mechanism of impaired astrocytic glutamate reuptake remains unclear. (2) Methods: We investigated the mechanism of the HMGB1/TLR4 axis in extracellular glutamate clearance in primary astrocytes exposed to ischemia/reperfusion by using OGD/R (oxygen-glucose deprivation/reoxygenation) model. (3) Results: OGD/R insult activated the HMGB1/TLR4 axis for reducing the activity of glutamate clearance by inhibiting GLAST (glutamate aspartate transporter) expression in primary astrocytes. Interestingly, OGD/R-untreated astrocytes showed impairment of glutamate clearance after exposure to exogenous HMGB1 or conditioned medium from OGD/R-treated astrocytes culture. Inhibition of HMGB1 or TLR4 effectively prevented impaired glutamate clearance, which was induced by OGD/R, exogenous HMGB1, or conditioned medium from OGD/R-treated astrocytes. Furthermore, glycyrrhizic acid attenuated OGD/R-induced impairment of astrocytic glutamate clearance mediated by the HMGB1-TLR4 axis. (4) Conclusion: The HMGB1/TLR4 axis is a potential target for the treatment of post-ischemic excitotoxicity caused by GLAST dysfunction in astrocytes.

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FYK-KOLODZIEJ, BOZENA, PU QIN, ARTURIK DZHAGARYAN, and ROBERTA G. POURCHO. "Differential cellular and subcellular distribution of glutamate transporters in the cat retina." Visual Neuroscience 21, no. 4 (July 2004): 551–65. http://dx.doi.org/10.1017/s0952523804214067.

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Retrieval of glutamate from extracellular sites in the retina involves at least five excitatory amino acid transporters. Immunocytochemical analysis of the cat retina indicates that each of these transporters exhibits a selective distribution which may reflect its specific function. The uptake of glutamate into Müller cells or astrocytes appears to depend upon GLAST and EAAT4, respectively. Staining for EAAT4 was also seen in the pigment epithelium. The remaining transporters are neuronal with GLT-1α localized to a number of cone bipolar, amacrine, and ganglion cells and GLT-1v in cone photoreceptors and several populations of bipolar cells. The EAAC1 transporter was found in horizontal, amacrine, and ganglion cells. Staining for EAAT5 was seen in the axon terminals of both rod and cone photoreceptors as well as in numerous amacrine and ganglion cells. Although some of the glutamate transporter molecules are positioned for presynaptic or postsynaptic uptake at glutamatergic synapses, others with localizations more distant from such contacts may serve in modulatory roles or provide protection against excitoxic or oxidative damage.

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Wahle, S., and W. Stoffel. "Membrane topology of the high-affinity L-glutamate transporter (GLAST-1) of the central nervous system." Journal of Cell Biology 135, no. 6 (December 15, 1996): 1867–77. http://dx.doi.org/10.1083/jcb.135.6.1867.

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The membrane topology of the high affinity, Na(+)-coupled L-glutamate/L-aspartate transporter (GLAST-1) of the central nervous system has been determined. Truncated GLAST-1 cDNA constructs encoding protein fragments with an increasing number of hydrophobic regions were fused to a cDNA encoding a reporter peptide with two N-glycosylation sites. The respective cRNA chimeras were translated in vitro and in vivo in Xenopus oocytes. Posttranslational N-glycosylation of the two reporter consensus sites monitors the number, size, and orientation of membrane-spanning domains. The results of our experiments suggest a novel 10-transmembrane domain topology of GLAST-1, a representative of the L-glutamate neurotransmitter transporter family, with its NH2 and COOH termini on the cytoplasmic side, six NH2-terminal hydrophobic transmembrane alpha-helices, and four COOH-terminal short hydrophobic domains spanning the bilayer predicted as beta-sheets.

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Wakabayashi, Maki, Toshio Hasegawa, Takuji Yamaguchi, Naoko Funakushi, Hajime Suto, Rie Ueki, Hiroyuki Kobayashi, Hideoki Ogawa, and Shigaku Ikeda. "Yokukansan, a Traditional Japanese Medicine, Adjusts Glutamate Signaling in Cultured Keratinocytes." BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/364092.

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Glutamate plays an important role in skin barrier signaling. In our previous study, Yokukansan (YKS) affected glutamate receptors in NC/Nga mice and was ameliorated in atopic dermatitis lesions. The aim of this study was to assess the effect of YKS on skin and cultured human keratinocytes. Glutamate concentrations in skin of YKS-treated and nontreated NC/Nga mice were measured. Then, glutamate release from cultured keratinocytes was measured, and extracellular glutamate concentrations in YKS-stimulated cultured human keratinocytes were determined. The mRNA expression levels of NMDA receptor 2D (NMDAR2D) and glutamate aspartate transporter (GLAST) were also determined in YKS-stimulated cultured keratinocytes. The glutamate concentrations and dermatitis scores increased in conventional mice, whereas they decreased in YKS-treated mice. Glutamate concentrations in cell supernatants of cultured keratinocytes increased proportionally to the cell density. However, they decreased dose-dependently with YKS. YKS stimulation increased NMDAR2D in a concentration-dependent manner. Conversely, GLAST decreased in response to YKS. Our findings indicate that YKS affects peripheral glutamate signaling in keratinocytes. Glutamine is essential as a transmitter, and dermatitis lesions might produce and release excess glutamate. This study suggests that, in keratinocytes, YKS controls extracellular glutamate concentrations, suppresses N-methyl-D-aspartate (NMDA) receptors, and activates glutamate transport.

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Suzuki, Gentaroh, Hiroshi Kawamoto, and Hisashi Ohta. "Development of a β-Lactamase Reporter Gene Assay for Metabotropic Glutamate Receptor 1 by Using Coexpression of Glutamate Transporter." Journal of Biomolecular Screening 15, no. 2 (January 19, 2010): 148–58. http://dx.doi.org/10.1177/1087057109356982.

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mGluR1 antagonists have been postulated to be novel CNS drugs, including antipsychotics. Toward this end, the authors developed a β-lactamase reporter assay to identify mGluR1 antagonists. β-Lactamase has several interesting features for high-throughput screening, including very high sensitivity and less well-to-well variation than other reporter enzymes. mGluR1-expressing Chinese hamster ovary (CHO) cells with the β-lactamase gene under control of the nuclear factor of activated T cells (NFAT) promoter (CHO-NFAT-bla-hmGluR1b) exhibited very high basal activity, resulting in an inadequate signal-to-basal (S/B) ratio. Coexpression of glutamate/aspartate transporter (GLAST) with mGluR1 in the cell line (CHO-NFAT-bla-hmGluR1b-GLAST) dramatically decreased basal activity and improved the S/B ratio (from 2- to 20-fold). The contribution of GLAST to lowering basal activity and increasing the S/B ratio was validated by the expression level of GLAST mRNA and by a GLAST inhibitor. Antagonistic activities of known mGluR1 antagonists in the β-lactamase reporter assay were comparable with those in the conventional Ca2+ mobilization assay. The Z′ factor of the β-lactamase reporter assay was 0.89 under optimized conditions. Taken together, the β-lactamase reporter assay with CHO-NFAT-bla-hmGluR1b-GLAST could be a novel high-throughput assay for mGluR1 antagonist screening. This is the first description of a successful β-lactamase reporter assay among all mGluR subtypes.

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Yu, Jun, Yan Yan, Yiye Chen, Yan Zheng, Xiaoyan Yu, Jialu Wang, Yafu Wang, et al. "A2AR Antagonists Upregulate Expression of GS and GLAST in Rat Hypoxia Model." BioMed Research International 2020 (October 26, 2020): 1–8. http://dx.doi.org/10.1155/2020/2054293.

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Background. The aim of this study was to research the effects of glutamine synthetase (GS) and glutamate aspartate transporter (GLAST) in rat Müller cells and the effects of an adenosine A2AR antagonist (SCH 442416) on GS and GLAST in hypoxia both in vivo and in vitro. Methods. This study used RT-PCR and Western blotting to quantify the expressions of GS and GLAST under different hypoxic conditions as well as the expressions of GS and GLAST at different drug concentrations. A cell viability assay was used to assess drug toxicity. Results. mRNA and protein expression of GS and GLAST in hypoxia Group 24 h was significantly increased. mRNA and protein expressions of GS and GLAST both increased in Group 1 μM SCH 442416 compared with other groups. One micromolar SCH 442416 could upregulate GS and GLAST’s activity in hypoxia both in vivo and in vitro. Conclusions. Hypoxia activates GS and GLAST in rat retinal Müller cells in a short time in vitro. (2) A2AR antagonists upregulate the activity of GS and GLAST in hypoxia both in vivo and in vitro.

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Namekata, Kazuhiko, Chikako Harada, Kuniko Kohyama, Yoh Matsumoto, and Takayuki Harada. "Interleukin-1 Stimulates Glutamate Uptake in Glial Cells by Accelerating Membrane Trafficking of Na+/K+-ATPase via Actin Depolymerization." Molecular and Cellular Biology 28, no. 10 (March 10, 2008): 3273–80. http://dx.doi.org/10.1128/mcb.02159-07.

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ABSTRACT Interleukin-1 (IL-1) is a mediator of brain injury induced by ischemia, trauma, and chronic neurodegenerative disease. IL-1 also has a protective role by preventing neuronal cell death from glutamate neurotoxicity. However, the cellular mechanisms of IL-1 action remain unresolved. In the mammalian retina, glutamate/aspartate transporter (GLAST) is a Na+-dependent, major glutamate transporter localized to Müller glial cells, and loss of GLAST leads to glaucomatous retinal degeneration (T. Harada, C. Harada, K. Nakamura, H. A. Quah, A. Okumura, K. Namekata, T. Saeki, M. Aihara, H. Yoshida, A. Mitani, and K. Tanaka, J. Clin. Investig. 117:1763-1770, 2007). We show here that IL-1 increases glutamate uptake in Müller cells by a mechanism that involves increased membrane Na+/K+-ATPase localization, required for counteracting the Na+-glutamate cotransport. IL-1 activated the p38 mitogen-activated protein kinase (MAPK)/capase 11 pathway, which destabilizes the actin cytoskeleton allowing Na+/K+-ATPase membrane redistribution. Furthermore, pretreatment with IL-1 protected retinal neurons from glutamate neurotoxicity through p38 MAPK signaling. Our observations suggested that IL-1 acts as a potential neuroprotective agent by modulating the functions of the glia-neuron network.

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Dąbrowska-Bouta, Beata, Grzegorz Sulkowski, Mikołaj Sałek, Magdalena Gewartowska, Marta Sidoryk-Węgrzynowicz, and Lidia Strużyńska. "Early Postnatal Exposure to a Low Dose of Nanoparticulate Silver Induces Alterations in Glutamate Transporters in Brain of Immature Rats." International Journal of Molecular Sciences 21, no. 23 (November 26, 2020): 8977. http://dx.doi.org/10.3390/ijms21238977.

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Due to strong antimicrobial properties, silver nanoparticles (AgNPs) are used in a wide range of medical and consumer products, including those dedicated for infants and children. While AgNPs are known to exert neurotoxic effects, current knowledge concerning their impact on the developing brain is scarce. During investigations of mechanisms of neurotoxicity in immature rats, we studied the influence of AgNPs on glutamate transporter systems which are involved in regulation of extracellular concentration of glutamate, an excitotoxic amino acid, and compared it with positive control—Ag citrate. We identified significant deposition of AgNPs in brain tissue of exposed rats over the post-exposure time. Ultrastructural alterations in endoplasmic reticulum (ER) and Golgi complexes were observed in neurons of AgNP-exposed rats, which are characteristics of ER stress. These changes presumably underlie substantial long-lasting downregulation of neuronal glutamate transporter EAAC1, which was noted in AgNP-exposed rats. Conversely, the expression of astroglial glutamate transporters GLT-1 and GLAST was not affected by exposure to AgNPs, but the activity of the transporters was diminished. These results indicate that even low doses of AgNPs administered during an early stage of life create a substantial risk for health of immature organisms. Hence, the safety of AgNP-containing products for infants and children should be carefully considered.

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Ueki, Toshiyuki, Zenji Kawakami, Hitomi Kanno, Yuji Omiya, Kazushige Mizoguchi, and Masahiro Yamamoto. "Yokukansan, a Traditional Japanese Medicine, Enhances the Glutamate Transporter GLT-1 Function in Cultured Rat Cortical Astrocytes." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/6804017.

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Astrocytes carry two glutamate transporters—GLAST and GLT-1—the latter of which is responsible for >90% of glutamate uptake activity in the brain; however, under culture conditions, the GLT-1 expression in astrocytes is exceedingly low, as is the glutamate uptake activity mediated by GLT-1. This study aimed to elucidate the effects of yokukansan (YKS) in relation to the GLT-1-mediated regulation of extracellular glutamate concentrations. Thus, we treated cultured astrocytes with tumor necrosis factor-α (TNF-α) and dibutyryl-cAMP (dBcAMP) (hereinafter, referred to as “TA”) to increase GLT-1 expression and then functionally examined how YKS would affect glutamate uptake ability derived from GLT-1. Contrary to expectations, although the TA treatments did not affect the uptake activity, YKS significantly augmented it. Conversely, GLAST-derived glutamate uptake was significantly reduced by TA treatments but was unaffected by YKS. Subsequently, we analyzed the GLT-1 protein and mRNA levels and found that TA treatments had significantly increased them, which were then further augmented by YKS. These findings suggest that YKS enhances GLT-1-derived glutamate transport functions in TA-treated cultured astrocytes and that this process entails increased GLT-1 protein and mRNA levels. This type of mechanism may contribute to the YKS-mediated regulation of extracellular glutamate concentrations.

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Bauer, Deborah E., Joshua G. Jackson, Elizabeth N. Genda, Misty M. Montoya, Marc Yudkoff, and Michael B. Robinson. "The glutamate transporter, GLAST, participates in a macromolecular complex that supports glutamate metabolism." Neurochemistry International 61, no. 4 (September 2012): 566–74. http://dx.doi.org/10.1016/j.neuint.2012.01.013.

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Jin, Zhen-Hua, Toshihiko Kikuchi, Kohichi Tanaka, and Toshimitsu Kobayashi. "Expression of Glutamate Transporter GLAST in the Developing Mouse Cochlea." Tohoku Journal of Experimental Medicine 200, no. 3 (2003): 137–44. http://dx.doi.org/10.1620/tjem.200.137.

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Zhou, Bo-Guang, and Michael D. Norenberg. "Ammonia downregulates GLAST mRNA glutamate transporter in rat astrocyte cultures." Neuroscience Letters 276, no. 3 (December 1999): 145–48. http://dx.doi.org/10.1016/s0304-3940(99)00816-2.

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Niederberger, Ellen, Achim Schmidtko, Ovidiu Coste, Claudiu Marian, Corina Ehnert, and Gerd Geisslinger. "The glutamate transporter GLAST is involved in spinal nociceptive processing." Biochemical and Biophysical Research Communications 346, no. 2 (July 2006): 393–99. http://dx.doi.org/10.1016/j.bbrc.2006.05.163.

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Lehre, Knut P., Svend Davanger, and Niels C. Danbolt. "Localization of the glutamate transporter protein GLAST in rat retina." Brain Research 744, no. 1 (January 1997): 129–37. http://dx.doi.org/10.1016/s0006-8993(96)01022-0.

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Chen, Xiaomin, Yue Wang, Fangfang Han, and Min Ke. "Cyanin Chloride Inhibits Hyperbaric Pressure-Induced Decrease of Intracellular Glutamate-Aspartate Transporter in Rat Retinal Müller Cells." Journal of Ophthalmology 2018 (October 31, 2018): 1–6. http://dx.doi.org/10.1155/2018/6128470.

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Purpose. Glaucoma is the leading cause of irreversible blindness throughout the world. The pathogenesis of glaucoma is complex, and neuroprotection is a crucial aspect of therapy. High concentrations of extracellular glutamate are toxic to the optic nerve. The glutamate-aspartate transporter (GLAST) in retinal Müller cells is involved in the development of glaucoma. Anthocyanin has been reported to protect retinal neurons. We hypothesize that cyanin chloride, a type of anthocyanin, can inhibit hyperbaric pressure-induced GLAST decreases in cultured rat retinal Müller cells and may serve as a potential neuroprotective agent in glaucoma treatment. Materials and Methods. Sprague Dawley rat Müller cells were cultured in a hyperbaric pressure device at 60 mmHg additional pressure and treated with cyanin chloride (10 μmol/L, 30 μmol/L, or 50 μmol/L) or vehicle for 2 hours. Cell survival rates (SRs) were evaluated by an MTT assay. GLAST mRNA and protein expression were determined by western blot and RT-PCR analyses, respectively. Results. Cell SR was significantly decreased in the 60 mmHg additional hyperbaric pressure group compared to the control group (P<0.01). Cyanin chloride treatment significantly improved SR under 60 mmHg additional pressure (P<0.01). GLAST mRNA and protein expression levels in Müller cells were significantly reduced in the 60 mmHg hyperbaric pressure group compared to the control group (P<0.01), but cyanin chloride significantly inhibited hyperbaric pressure-induced decreases in GLAST expression (P<0.01). Conclusion. Our results support our hypothesis and demonstrate that cyanin chloride can protect rat retinal Müller cells from hyperbaric pressure-induced decreases of GLAST.

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Cholet, Nathalie, Luc Pellerin, Egbert Welker, Pierre Lacombe, Jacques Seylaz, Pierre Magistretti, and Gilles Bonvento. "Local Injection of Antisense Oligonucleotides Targeted to the Glial Glutamate Transporter GLAST Decreases the Metabolic Response to Somatosensory Activation." Journal of Cerebral Blood Flow & Metabolism 21, no. 4 (April 2001): 404–12. http://dx.doi.org/10.1097/00004647-200104000-00009.

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The mechanisms responsible for the local increase in brain glucose utilization during functional activation remain unknown. Recent in vitro studies have identified a new signaling pathway involving an activation of glial glutamate transporters and enhancement of neuron–astrocyte metabolic interactions that suggest a putative coupling mechanism. The aim of the present study was to determine whether one of the glutamate transporters exclusively expressed in astrocytes, GLAST, is involved in the neurometabolic coupling in vivo. For this purpose, rats were microinjected into the posteromedial barrel subfield (PMBSF) of the somatosensory cortex with GLAST antisense or random phosphorothioate oligonucleotides. The physiologic activation was performed by stimulating the whisker-to-barrel pathway in anesthetized rats while measuring local cerebral glucose utilization by quantitative autoradiography in the PMBSF. Twenty-four hours after injection of two different antisense GLAST oligonucleotide sequences, and despite the presence of normal whisker-related neuronal activity in the PMBSF, the metabolic response to whisker stimulation was decreased by more than 50%. Injection of the corresponding random sequences still allowed a significant increase in glucose utilization in the activated area. The present study highlights the contribution of astrocytes to neurometabolic coupling in vivo. It provides evidence that glial glutamate transporters are key molecular components of this coupling and that neuronal glutamatergic activity is an important determinant of energy utilization. Results indicate that astrocytes should also be considered as possible sources of altered brain metabolism that could explain the distinct imaging signals observed in some pathologic situations

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Lawton, D. Maxwell, David N. Furness, Bernd Lindemann, and Carole M. Hackney. "Localization of the glutamate-aspartate transporter, GLAST, in rat taste buds." European Journal of Neuroscience 12, no. 9 (September 2000): 3163–71. http://dx.doi.org/10.1046/j.1460-9568.2000.00207.x.

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Gottlieb, M., M. Domercq, and C. Matute. "Altered Expression of the Glutamate Transporter EAAC1 in Neurons and Immature Oligodendrocytes after Transient Forebrain Ischemia." Journal of Cerebral Blood Flow & Metabolism 20, no. 4 (April 2000): 678–87. http://dx.doi.org/10.1097/00004647-200004000-00005.

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Glutamate uptake is reduced during ischemia because of perturbations of ionic gradients across neuronal and glial membranes. Using immunohistochemical and Western blot analyses, the authors examined the expression of the glutamate transporters EAAC1, GLAST, and GLT-1 in the rat hippocampus and cerebral cortex 8 hours and 1 to 28 days after transient forebrain ischemia. Densitometric analysis of immunoblots of CA1 homogenates showed a moderate increase in EAAC1 protein levels early after the insult. Consistently, it was observed that EAAC1 immunostaining in CA1 pyramidal neurons was more intense after 8 hours and 1 day of reperfusion and reduced at later postischemia stages. A similar transient increase of EAAC1 immunolabeling was detected in layer V pyramidal neurons of the cerebral cortex. In addition, the authors observed that EAAC1 also was located in oligodendroglial progenitor cells in subcortical white matter. The number of EAAC1-labeled cells in this region was increased after 3 and 28 days of reperfusion. Finally, changes in GLAST and GLT-1 expression were not observed in the CA1 region after ischemia using immunohistochemical study or immunoblotting. Enhanced expression of EAAC1 may be an adaptive response to increased levels of extracellular glutamate during ischemia.

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Masocha, Willias. "Astrocyte activation in the anterior cingulate cortex and altered glutamatergic gene expression during paclitaxel-induced neuropathic pain in mice." PeerJ 3 (October 22, 2015): e1350. http://dx.doi.org/10.7717/peerj.1350.

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Spinal astrocyte activation contributes to the pathogenesis of paclitaxel-induced neuropathic pain (PINP) in animal models. We examined glial fibrillary acidic protein (GFAP; an astrocyte marker) immunoreactivity and gene expression of GFAP, glutamate transporters and receptor subunits by real time PCR in the anterior cingulate cortex (ACC) at 7 days post first administration of paclitaxel, a time point when mice had developed thermal hyperalgesia. The ACC, an area in the brain involved in pain perception and modulation, was chosen because changes in this area might contribute to the pathophysiology of PINP. GFAP transcripts levels were elevated by more than fivefold and GFAP immunoreactivity increased in the ACC of paclitaxel-treated mice. The 6 glutamate transporters (GLAST, GLT-1 EAAC1, EAAT4, VGLUT-1 and VGLUT-2) quantified were not significantly altered by paclitaxel treatment. Of the 12 ionotropic glutamate receptor subunits transcripts analysed 6 (GLuA1, GLuA3, GLuK2, GLuK3, GLuK5 and GLuN1) were significantly up-regulated, whereas GLuA2, GLuK1, GLuK4, GLuN2A and GLuN2B were not significantly altered and GLuA4 was lowly expressed. Amongst the 8 metabotropic receptor subunits analysed only mGLuR8 was significantly elevated. In conclusion, during PINP there is astrocyte activation, with no change in glutamate transporter expression and differential up-regulation of glutamate receptor subunits in the ACC. Thus, targeting astrocyte activation and the glutamatergic system might be another therapeutic avenue for management of PINP.

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Sun, Dong, Zhi-Bing Tan, Xiang-Dong Sun, Zhi-Peng Liu, Wen-Bing Chen, Leena Milibari, Xiao Ren, et al. "Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response." Proceedings of the National Academy of Sciences 118, no. 16 (April 13, 2021): e2022921118. http://dx.doi.org/10.1073/pnas.2022921118.

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Epilepsy, a common neurological disorder, is featured with recurrent seizures. Its underlying pathological mechanisms remain elusive. Here, we provide evidence for loss of neogenin (NEO1), a coreceptor for multiple ligands, including netrins and bone morphological proteins, in the development of epilepsy. NEO1 is reduced in hippocampi from patients with epilepsy based on transcriptome and proteomic analyses. Neo1 knocking out (KO) in mouse brains displays elevated epileptiform spikes and seizure susceptibility. These phenotypes were undetectable in mice, with selectively depleted NEO1 in excitatory (NeuroD6-Cre+) or inhibitory (parvalbumin+) neurons, but present in mice with specific hippocampal astrocytic Neo1 KO. Additionally, neurons in hippocampal dentate gyrus, a vulnerable region in epilepsy, in mice with astrocyte-specific Neo1 KO show reductions in inhibitory synaptic vesicles and the frequency of miniature inhibitory postsynaptic current(mIPSC), but increase of the duration of miniature excitatory postsynaptic current and tonic NMDA receptor currents, suggesting impairments in both GABAergic transmission and extracellular glutamate clearance. Further proteomic and cell biological analyses of cell-surface proteins identified GLAST, a glutamate–aspartate transporter that is marked reduced in Neo1 KO astrocytes and the hippocampus. NEO1 interacts with GLAST and promotes GLAST surface distribution in astrocytes. Expressing NEO1 or GLAST in Neo1 KO astrocytes in the hippocampus abolishes the epileptic phenotype. Taken together, these results uncover an unrecognized pathway of NEO1-GLAST in hippocampal GFAP+ astrocytes, which is critical for GLAST surface distribution and function, and GABAergic transmission, unveiling NEO1 as a valuable therapeutic target to protect the brain from epilepsy.

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Leonova, Julia, Thorleif Thorlin, N. David Åberg, Peter S. Eriksson, Lars Rönnbäck, and Elisabeth Hansson. "Endothelin-1 decreases glutamate uptake in primary cultured rat astrocytes." American Journal of Physiology-Cell Physiology 281, no. 5 (November 1, 2001): C1495—C1503. http://dx.doi.org/10.1152/ajpcell.2001.281.5.c1495.

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Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is also known to induce a wide spectrum of biological responses in nonvascular tissue. In this study, we found that ET-1 (100 nM) inhibited the glutamate uptake in cultured astrocytes expressing the glutamate/aspartate transporter (GLAST); astrocytes did not express the glutamate transporter-1 (GLT-1). The V maxand the K m of the glutamate uptake were reduced by 57% and 47%, respectively. Application of the ETA and ETB receptor antagonists BQ-123 and BQ-788 partly inhibited the ET-1-evoked decrease in the glutamate uptake, whereas the nonspecific ET receptor antagonist bosentan completely inhibited this decrease. Incubation of the cultures with pertussis toxin abolished the effect of ET-1 on the uptake. The ET-1-induced decrease in the glutamate uptake was independent of extracellular free Ca2+concentration, whereas the intracellular Ca2+ antagonists thapsigargin and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester abolished the effect of ET-1 on the glutamate uptake. Incubation with the protein kinase C (PKC) antagonist staurosporine, but not with the fatty acid-binding protein bovine serum albumin, prevented the ET-1-induced decrease in the glutamate uptake. These results suggest that ET-1 impairs the high-affinity glutamate uptake in cultured astrocytes through a G protein-coupled mechanism, involving PKC and changes in intracellular Ca2+.

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Owe, Simen Gylterud, Païkan Marcaggi, and David Attwell. "The ionic stoichiometry of the GLAST glutamate transporter in salamander retinal glia." Journal of Physiology 577, no. 2 (November 24, 2006): 591–99. http://dx.doi.org/10.1113/jphysiol.2006.116830.

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Watanabe, Takemi, Kiyoshi Morimoto, Toru Hirao, Hiroshi Suwaki, Kei Watase, and Kohichi Tanaka. "Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice." Brain Research 845, no. 1 (October 1999): 92–96. http://dx.doi.org/10.1016/s0006-8993(99)01945-9.

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Watanabe, Takemi, Kiyoshi Morimoto, Toru Hirao, Hiroshi Suwaki, Kei Watase, and Kohi chi Tanaka. "Amygdala-Kindling and Pentylenetetrazole-Induced Seizures in Glutamate Transporter GLAST-Deficient Mice." Epilepsia 41, s9 (September 2000): 49–50. http://dx.doi.org/10.1111/j.1528-1157.2000.tb02222.x.

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Matsuura, Sigeru, Yuji Ikegaya, Maki K. Yamada, Nobuyoshi Nishiyama, and Norio Matsuki. "Endothelin downregulates the glutamate transporter GLAST in cAMP-differentiated astrocytes in vitro." Glia 37, no. 2 (December 19, 2001): 178–82. http://dx.doi.org/10.1002/glia.10020.

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Dematteis, Giulia, Elena Restelli, Roberto Chiesa, Eleonora Aronica, Armando A. Genazzani, Dmitry Lim, and Laura Tapella. "Calcineurin Controls Expression of EAAT1/GLAST in Mouse and Human Cultured Astrocytes through Dynamic Regulation of Protein Synthesis and Degradation." International Journal of Molecular Sciences 21, no. 6 (March 23, 2020): 2213. http://dx.doi.org/10.3390/ijms21062213.

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Alterations in the expression of glutamate/aspartate transporter (GLAST) have been associated with several neuropathological conditions including Alzheimer’s disease and epilepsy. However, the mechanisms by which GLAST expression is altered are poorly understood. Here we used a combination of pharmacological and genetic approaches coupled with quantitative PCR and Western blot to investigate the mechanism of the regulation of GLAST expression by a Ca2+/calmodulin-activated phosphatase calcineurin (CaN). We show that treatment of cultured hippocampal mouse and fetal human astrocytes with a CaN inhibitor FK506 resulted in a dynamic modulation of GLAST protein expression, being downregulated after 24–48 h, but upregulated after 7 days of continuous FK506 (200 nM) treatment. Protein synthesis, as assessed by puromycin incorporation in neo-synthesized polypeptides, was inhibited already after 1 h of FK506 treatment, while the use of a proteasome inhibitor MG132 (1 μM) shows that GLAST protein degradation was only suppressed after 7 days of FK506 treatment. In astrocytes with constitutive genetic ablation of CaN both protein synthesis and degradation were significantly inhibited. Taken together, our data suggest that, in cultured astrocytes, CaN controls GLAST expression at a posttranscriptional level through regulation of GLAST protein synthesis and degradation.

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Erikson, Keith, and Michael Aschner. "Manganese Causes Differential Regulation of Glutamate Transporter (GLAST) Taurine Transporter and Metallothionein in Cultured Rat Astrocytes." NeuroToxicology 23, no. 4-5 (October 2002): 595–602. http://dx.doi.org/10.1016/s0161-813x(02)00012-8.

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Rauen, T., W. Rowland Taylor, Kirsten Kuhlbrodt, and Michael Wiessner. "High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance." Cell and Tissue Research 291, no. 1 (December 12, 1997): 19–31. http://dx.doi.org/10.1007/s004410050976.

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Kashem, Mohammed Abul, Omar Šerý, David V. Pow, Benjamin D. Rowlands, Caroline D. Rae, and Vladimir J. Balcar. "Actions of Alcohol in Brain: Genetics, Metabolomics, GABA Receptors, Proteomics and Glutamate Transporter GLAST/EAAT1." Current Molecular Pharmacology 14, no. 2 (December 31, 2020): 138–49. http://dx.doi.org/10.2174/1874467213666200424155244.

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We present an overview of genetic, metabolomic, proteomic and neurochemical studies done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase B (MAO B) and several other enzymes were identified as associated with altered risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk of developing deficiences in colour vision sometimes observed in alcoholics. Metabolomic studies of acute ethanol effects on guinea pig brain cortex in vitro, lead to the identification of specific subtypes of GABA(A) receptors involved in the actions of alcohol at various doses. Acute alcohol affected energy metabolism, oxidation and the production of actaldehyde and acetate; this could have specific consequences not only for the brain energy production/utilization but could influence the cytotoxicity of alcohol and impact the epigenetics (histone acetylation). It is unlikely that brain metabolism of ethanol occurs to any significant degree; the reduction in glucose metabolism following alcohol consumption is due to ethanol effects on receptors, such as α4β3δ GABA(A) receptors. Metabolomics using post-mortem human brain indicated that the catecholaminergic signalling may be preferentially affected by chronic excessive drinking. Changes in the levels of glutathione were consistent with the presence of severe oxidative stress. Proteomics of the post-mortem alcoholic brains identified a large number of proteins, the expression of which was altered by chronic alcohol, with those associated with brain energy metabolism among the most numerous. Neurochemical studies found the increased expression of glutamate transporter GLAST/EAAT1 in brain as one of the largest changes caused by alcoholism. Given that GLAST/EAAT1 is one of the most abundant proteins in the nervous tissue and is intimately associated with the function of the excitatory (glutamatergic) synapses, this may be among the most important effects of chronic alcohol on brain function. It has so far been observed mainly in the prefrontal cortex. We show several experiments suggesting that acute alcohol can translocate GLAST/EAAT1 in astrocytes towards the plasma membrane (and this effect is inhibited by the GABA(B) agonist baclofen) but neither the mechanism nor the specificity (to alcohol) of this phenomenon have been established. Furthermore, as GLAST/EAAT1 is also expressed in testes and sperm (and could also be affected there by chronic alcohol), the levels of GLAST/EAAT1 in sperm could be used as a diagnostic tool in testing the severity of alcoholism in human males. We conclude that the reviewed studies present a unique set of data which could help to predict the risk of developing alcohol dependence (genetics), to improve the understanding of the intoxicating actions of alcohol (metabolomics), to aid in assessing the extent of damage to brain cells caused by chronic excessive drinking (metabolomics and proteomics) and to point to molecular targets that could be used in the treatment and diagnosis of alcoholism and alcohol addiction.

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Gegelashvili, Marina, Anna Rodriguez-Kern, Iryna Pirozhkova, Jian Zhang, Luther Sung, and Georgi Gegelashvili. "High-affinity glutamate transporter GLAST/EAAT1 regulates cell surface expression of glutamine/neutral amino acid transporter ASCT2 in human fetal astrocytes." Neurochemistry International 48, no. 6-7 (May 2006): 611–15. http://dx.doi.org/10.1016/j.neuint.2005.12.033.

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Hakuba, Nobuhiro, Kenichiro Koga, Kiyofumi Gyo, Shin-ichi Usami, and Kohichi Tanaka. "Exacerbation of Noise-Induced Hearing Loss in Mice Lacking the Glutamate Transporter GLAST." Journal of Neuroscience 20, no. 23 (December 1, 2000): 8750–53. http://dx.doi.org/10.1523/jneurosci.20-23-08750.2000.

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Kinoshita, Nagatoki, Kazushi Kimura, Naoya Matsumoto, Masahiko Watanabe, Masahiro Fukaya, and Chizuka Ide. "Mammalian septin Sept2 modulates the activity of GLAST, a glutamate transporter in astrocytes." Genes to Cells 9, no. 1 (January 2004): 1–14. http://dx.doi.org/10.1111/j.1356-9597.2004.00696.x.

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Journal articles on the topic 'Glutamate transporter GLAST'

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