Abstract
The functional activity in the brain is primarily composed of an interplay between excitation and inhibition. In any given region the output is based upon a complex processing of incoming signals that require both excitatory and inhibitory units. Moreover, these units must be regulated and balanced such that an integrated and finely tuned response is generated. In each of these units or synapses the activity depends on biosynthesis, release, receptor interaction, and inactivation of the neurotransmitter in question; thus, it is easily understood that each of these processes needs to be highly regulated and controlled. It is interesting to note that in case of the most prevailing neurotransmitters, glutamate and GABA, which mediate excitation and inhibition, respectively, the inactivation process is primarily maintained by highly efficient, high-affinity transport systems capable of maintaining transmembrane concentration gradients of these amino acids of 104–105-fold. The demonstration of the presence of transporters for glutamate and GABA in both neuronal and astrocytic elements naturally raises the question of the functional importance of the astrocytes in the regulation of the level of the neurotransmitters in the synaptic cleft and hence for the activity of excitatory and inhibitory neurotransmission. Obviously, this discussion has important implications for the understanding of the role of astrocytes in disease states in which imbalances between excitation and inhibition are a triggering factor, for example, epilepsy and neurodegeneration.
REFERENCES
Logan, W. J. and Snyder, S. H. 1972. High affinity uptake systems for glycine, glutamic and aspartic acids in synaptosomes of rat central nervous tissues. Brain Res. 42:413–431.
Henn, F. A. and Hamberger, A. 1971. Glial cell function: uptake of transmitter substances. Proc. Natl. Acad. Sci. USA 68:2686–2690.
Henn, F. A., Goldstein, M. N., and Hamberger, A. 1974. Uptake of the neurotransmitter candidate glutamate by glia. Nature 249:663–664.
Schousboe, A., Hertz, L., and Svenneby, G. 1977. Uptake and metabolism of GABA in astrocytes cultured from dissociated mouse brain hemispheres. Neurochem. Res. 2:217–229.
Schousboe, A., Svenneby, G., and Hertz, L. 1977. Uptake and metabolism of glutamate in astrocytes cultured from dissociated mouse brain hemispheres. J. Neurochem. 29:999–1005.
Hertz, L., Schousboe, A., Boechler, N., Mukerji, S., and Fedoroff, S. 1978. Kinetic characteristics of the glutamate uptake into normal astrocytes in cultures. Neurochem. Res. 3:1–14.
Danbolt, N. C. 1994. The high-affinity uptake system for excitataory amino acids in the brain. Prog. Neurobiol. 44:377–396.
Danbolt, N. C. 2001. Glutamate uptake. Progr. Neurobiol. 65:1–105.
Guastella, J., Nelson, N., Nelson, H., Czyzyk, L., Keynan, S., Miedel, M. C., Davidson, N., Lester, H. A., and Kanner, B. I. 1990. Cloning and expression of a rat brain GABA transporter. Science 249:1303–1306.
Blakely, R. D., Berson, H. E., Fremeau, R. T., Caron, M. G., Peek, M. M., Prince, H. K., and Bradley, C. C. 1991. Cloning and expression of a functional serotonin transporter from rat brain. Nature 354:66–70.
Kilty, J., Lorang, D., and Amara, S. G. 1991. Cloning and expression of a cocaine-sensitive dopamine transporter. Science 254:578–579.
Storck, T., Schulte, S., Hofmann, K., and Stoffel, W. 1992. Structure, expression, and functional analysis of a Na+-dependent glutamate/aspartate transporter from rat brain. Proc. Natl. Acad. Sci. USA 89:10955–10959.
Pines, G., Danbolt, N. C., Bjorås, M., Zhang, Y., Bendahan, A., Eide, L., Koepsell, H., Storm-Mathisen, J., Seeberg, E., and Kanner, B. I. 1992. Cloning and expression of a rat brain L-glutamate transporter. Nature 360:464–467.
Kanai, Y. and Hediger, M. A. 1992. Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360:467–471.
Fairman, W. A., Vandenberg, R. J., Arriza, J. L., Kavanaugh, M. P., and Amara, S. G. 1995. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375:599–603.
Arriza, J. L., Eliasof, S., Kavanaugh, M. P., and Amara, S. G. 1997. Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc. Natl. Acad. Sci. USA 94:4155–4160.
Gegelashvili, G. and Schousboe, A. 1998. Cellular distribution and kinetic properties of high-affinity glutamate transporters. Brain Res. Bull. 45:233–238.
Lehre, K. P., Levy, L. M., Ottersen, O. P., Storm-Mathisen, J., and Danbolt, N. C. 1995. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J. Neurosci. 15:1835–1853.
Lehre, K. P. and Danbolt, N. C. 1998. The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J. Neurosci. 18:8751–8757.
Levy, L. M. 2002. Structure, function and regulation of glutamate transporters. Pages 307–336, in Egebjerg, J., Schousboe, A., and Krogsgaard-Larsen, P. (eds.), Glutamate and GABA Receptors and Transporters. Structure, Function and Pharmacology, Taylor and Francis, London.
Northington, F. J., Traystman, R. J., Koehler, R. C., and Martin, L. J. 1999. GLT1, glial glutamate transporter, is transiently expressed in neurons and develops astrocyte specificity only after midgestation in the bovine fetal brain. J. Neurobiol. 39:515–526.
Plachez, C., Danbolt, N. C., and Recasens, M. 2000. Transient expression of the glial glutamate transporters GLAST and GLT in hippocampal neurons in primary culture. J. Neurosci. Res. 59:587–593.
Rothstein, J. D., Martin, L., Levey, A. I., Dykes-Hoberg, M., Jin, L., Wu, D., Nash, N., and Kuncl, R. W. 1994. Localization of neuronal and glial glutamate transporters. Neuron 13:713–725.
Hertz, L. 1979. Functional interactions between neurons and astrocytes: I. Turnover and metabolism of putative amino acid transmitters. Prog. Neurobiol. 13:277–323.
Schousboe, A. 1981. Transport and metabolism of glutamate and GABA in neurons and glial cells. Int. Rev. Neurobiol. 22:1–45.
Yamada, K., Watanabe, M., Shibata, T., Tanaka, K., Wada, K., and Inoue, Y. 1996. EAAT4 is a post-synaptic glutamate transporter at Purkinje cell synapses. Neuroreport 7:2013–2017.
Dehnes, Y., Chaudhry, F. A., Ullensvang, K., Lehre, K. P., Storm-Mathisen, J., and Danbolt, N. C. 1998. The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J. Neurosci. 18:3606–3619.
Rauen, T., Fischer, F., and Wiessner, M. 1999. Glia-neuron interaction by high-affinity glutamate transporters in neurotransmission. Adv. Exp. Med. Biol. 468:81–95.
Tong, G. and Jahr, C. E. 1994. Block of glutamate transporters potentiates postsynaptic excitation. Neuron 13:1195–1203.
Wadiche, J. I., Arriza, J. L., Amara, S. G., and Kavanaugh, M. P. 1995. Kinetics of a human glutamate transporter. Neuron 14:1019–1027.
Benveniste, H., Drejer, J., Schousboe, A., and Diemer, N. H. 1984. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J. Neurochem. 43:1369–1374.
Hagberg, H., Lehmann, A., Sandberg, M., Nyström, B., Jacobsen, I., and Hamberger, A. 1985. Ischemia-induced shift of inhibitory and excitatory amino acids from intra-to extracellular compartments. J. Cereb. Blood Flow Metab. 5:413–419.
Sandberg, M., Butcher, S. P., and Hagberg, H. 1986. Extracellular overflow of neuroactive amino acids during severe insulin-induced hypoglycemia: in vivo dialysis of rat hippocampus. J. Neurochem. 47:178–184.
Gegelashvili, G. and Schousboe, A. 1997. High-affinity glutamate transporters: regulation of expression and activity. Mol. Pharmacol. 52:6–15.
Gegelashvili, G., Robinson, M. B., Trotti, D., and Rauen, T. 2001. Regulation of glutamate transporters in health and disease. Prog. Brain Res. 132:267–286.
Rothstein, J. D., Van Kammen, M., Levey, A. I., Martin, L. J., and Kuncl, R. W. 1995. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38:73–84.
Choi, D. W. and Rothman, S. M. 1990. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci. 13:171–182.
Schousboe, A. and Frandsen, A. 1995. Glutamate receptors and neurotoxicity. Pages 239–251, in Stone, T. W. (ed.), CNS Neurotransmitters and Neuromodulators: Glutamate, CRC Press, Boca Raton, FL.
Wang, G. J., Chung, H. J., Schnuer, J., Pratt, K., Zable, A. C., Kavanaugh, M. P., and Rosenberg, P. A. 1998. High affinity glutamate transport in rat cortical neurons in culture. Mol. Pharmacol. 53:88–96.
Chen, W., Aoki, C., Mahadomrongkul, V., Gruber, C. E., Wang, G. J., Blitzblau, R., Irwin, N., and Rosenberg, P. A. 2002. Expression of a variant form of the glutamate transporter GLT1 in neuronal cultures and in neurons and astrocytes in the rat brain. J. Neurosci. 22:2142–2152.
Drejer, J., Meier, E., and Schousboe, A. 1983. Novel neuron-related regulatory mechanisms for astrocytic glutamate and GABA high affinity uptake. Neurosci. Lett. 37:301–306.
Gegelashvili, G., Danbolt, N. C., and Schousboe, A. 1997. Neuronal soluble factors differentially regulate the expression of the GLT1 and GLAST glutamate transporters in cultured astroglia. J. Neurochem. 69:2612–2615.
Swanson, R. A., Liu, J., Miller, J. W., Rothstein, J. D., Farrel, K., Stein, B. A., and Longuemare, M. C. 1997. Neuronal regulation of glutamate transporter subtype expression in astrocytes. J. Neurosci. 17:932–940.
Schlag, B. D., Vondrasek, J. R., Munir, M., Kalandadze, A., Zelenaia, O. A., Rothstein, J. D., and Robinson, M. B. 1998. Regulation of the glial Na+-dependent glutamate transporters by cyclic AMP analogs and neurons. Mol. Pharmacol. 53:355–369.
Gegelashvili, G., Civenni, G., Racagni, G., Danbolt, N. C., Schousboe, I., and Schousboe, A. 1996. Glutamate receptor agonists up-regulate glutamate transporter glast in astrocytes. Neuroreport 8:261–265.
Gegelashvili, G., Dehnes, Y., Danbolt, N. C., and Schousboe, A. 2000. The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem. Int. 37:163–170.
Dowd, L. A. and Robinson, M. B. 1996. Rapid stimulation of EAAC1–mediated Na+-dependent L-glutamate transport activity in C6 glioma cells by phorbol ester. J. Neurochem. 67:508–516.
Gonsalez, M. I. and Ortega, A. 1997. Regulation of the Na+-dependent high affinity glutamate/aspartate transporter in cultured Bergmann glia by phorbol esters. J. Neurosci. Res. 50:585–590.
Gonsalez, M. I., Lopez-Colome, A. M., and Ortega, A. 1999. Sodium-dependent glutamate transport in Müller glial cells: regulation by phorbol esters. Brain Res. 831:140–145.
Davis, K. E., Sraff, D. J., Weinstein, E. A., Bannermann, P. G., Correale, D. M., Rothstein, J. D., and Robinson, M. B. 1998. Multiple signaling pathways regulate cell surface expression and activity of the excitatory amino acid carrier 1 subtype of Glu transporter in C6 glioma. J. Neurosci. 18:2475–2485.
Schousboe, A. and Kanner, B. 2002. GABA transporters: functional and pharmacological properties. Pages 337–349, in Egebjerg, J., Schousboe, A., and Krogsgaard-Larsen, P. (eds.), Glutamate and GABA Receptors and Transporters, Taylor & Francis Publ., London, UK.
Schousboe, A. and Westergaard, N. 1995. Transport of neuro-active amino acids in astrocytes. Pages 246–258, in Kettenmann, H. and Ransom, B. (eds.), Neuroglia, Oxford University Press, New York.
Hertz, L. and Schousboe, A. 1987. Primary cultures of GABA-ergic and glutamatergic neurons as model systems to study neurotransmitter functions: I. Differentiated cells. Pages 19–31, in Vernadakis, A., Privat, A., Lauder, J. M., Timiras, P. S., and Giacobini, E. (eds.), Model Systems of Development and Aging of the Nervous System, M. Nijhoff Publ. Comp., Boston, MD.
Gram, L., Larsson, O. M., Johnsen, A. H., and Schousboe, A. 1988. Effects of valproate, vigabatrin and amino oxyacetic acid on release of endogenous and exogenous GABA from cultured neurons. Epilepsy Res. 2:87–95.
Minelli, A., DeBiasi, S., Brecha, N. C., Zuccarello, L. V., and Conti, F. 1996. GAT-3, a high-affinity GABA plasma membrane transporter, is localized to astrocytic processes, and is not confined to the vicinity of GABAergic synapses in the cerebral cortex. J. Neurosci. 16:6255–6264.
Ribak, C. E., Tong, W. M., and Brecha, N. C. 1996. GABA plasma membrane transporters, GAT-1 and GAT-3, display different distributions in the rat hippocampus. J. Comp. Neurol. 367:595–606.
Ribak, C. E., Tong, W. M., and Brecha, N. C. 1996. Astrocytic processes compensate for the apparent lack of GABA transporters in the axon terminals of cerebellar Purkinje cells. Anat. Embryol. 193:379–390.
De Biasi, S., Vitellaro-Zuccarello, L., and Brecha, N. C. 1998. Immunoreactivity for the GABA transporter-1 and GABA transporter-3 is restricted to astrocytes in the rat thalamus: a light and electron-microscopic immunolocalization. Neuroscience 83:815–828.
Borden, L. A. 1996. GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem. Int. 29:335–356.
Norenberg, M. D., Vastag, M., and Zhou, B.-G. 2000. GABA Transporters in cultured rat astrocytes and neurons. J. Neurochem. 74 (Suppl.):S80.
Ebert, U. and Krnjevic, K. 1990. Systemic CI-966, a new gamma-aminobutyric acid uptake blocker, enhances gamma-aminobutyric acid action in CA1 pyramidal layer in situ. Can. J. Physiol. Pharmacol. 68:1194–1199.
Mitchell, S. J. and Silver, R. A. 2000. GABA spillover from single inhibitory axons suppresses low-frequency excitatory transmission at the cerebellar glomerulus. J. Neurosci. 20:8651–8658.
Rossi, D. J. and Hamann, M. 1998. Spillover-mediated transmission at inhibitory synapses promoted by high affinity α6 subunit GABAA receptors and glomerular geometry. Neuron 20:783–795.
Ichinose, T. and Lukasiewicz, P. D. 2002. GABA transporters regulate inhibition in the retina by limiting GABAC receptor activation. J. Neurosci. 22:3285–3292.
Fink-Jensen, A., Suzdak, P. D., Sweberg, M. D., Judge, M. E., Hansen, L., and Nielsen, P. G. 1992. The GABA uptake inhibitor, TGB, increases extracellular brain levels of GABA in awake rats. Eur. J. Pharmacol. 20:197–201.
Richards, D. A. and Bowery, N. G. 1996. Comparative effects of the GABA uptake inhibitors, tiagabine and NNC-711, on extracellular GABA levels in the rat ventrolateral thalamus. Neurochem. Res. 21:135–140.
Juhász, G., Kékesi, K. A., Nyitrai, G., Dobolyi, A., Krogsgaard-Larsen, P., and Schousboe, A. 1997. Differential effects of nipecotic acid and 4,5,6,7–tetrahydroisoxazolo[4,5–c]pyridin-3–ol on extracellular γ-aminobutyrate levels in rat thalamus. Eur. J. Pharmacol. 331:139–144.
Iversen, L. L. and Kelly, J. S. 1975. Uptake and metabolism of γ-aminobutyric acid by neurones and glial cells. Biochem. Pharmacol. 24:933–938.
Falch, E., Perregaard, J., Frølund, B., Søkilde, B., Buur, A., Hansen, L. M., Frydenvang, K., Brehm, L., Bolvig, T., Larsson, O. M., Sanchez, C., White, H. S., Schousboe, A., and Krogsgaard-Larsen, P. 1999. Selective inhibitors of glial GABA uptake: Synthesis, absolute stereochemistry and pharmacology of the enantiomers of 3–hydroxy-4–amino-4,5,6,7–tetrahydro-1, 2–benzisoxazole (Exo-THPO) and analogues. J. Med. Chem. 42:5402–5414.
White, H. S., Sarup, A., Bolvig, T., Kristensen, A. S., Petersen, G., Nelson, N., Pickering, D. S., Larsson, O. M., Frølund, B., Krogsgaard-Larsen, P., and Schousboe, A. 2002. Correlation between anticonvulsant activity and inhibitory action on glial GABA uptake of the highly selective mouse GAT1 inhibitor 3–hydroxy-4–amino-4,5,6,7–tetrahydro-1,2–benzisoxazole (exo-THPO) and its N-alkylated analogs. J. Pharmacol. Exp. Therap. 302, 636–644.
Meldrum, B. S. 1975. Epilepsy and γ-aminobutyric acid-mediated inhibition. Int. Rev. Neurobiol. 17:1–36.
Wood, J. D. 1975. The role of gamma-aminobutyric acid in the mechanism of seizures. Prog Neurobiol. 5:77–95.
Löscher, W. 1998. New visions in the pharmacology of anticonvulsion. Eur. J. Pharmacol. 342:1–13.
Suszdak, P. D. and Jansen, J. A. 1995. A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia 36:612–626.
Braestrup, C., Nielsen, E. B., Sonnewald, U., Knutsen, L. J. S., Andersen, K. E., Jansen, J. A., Frederiksen, K., Andersen, P. H., Mortensen, A., and Suzdak, P. D. 1990. (R)-N-[4,4–bis(3–methyl-2–thienyl)but-3–en-1–yl]nipecotic acid binds with high affinity to the brain γ-aminobutyric acid uptake carrier, J. Neurochem. 54:639–647.
Schousboe, A. 1979. Effects of GABA analogues on the high-affinity uptake of GABA in astrocytes in primary cultures. Pages 219–237, in Mandel, P. and De Feudis, F. V. (eds.), GABA: Biochemistry and CNS Function, Plenum Publishing, New York.
Schousboe, A., Larsson, O. M., Wood, J. D., and Krogsgaard-Larsen, P. 1983. Transport and metabolism of GABA in neurons and glia: implications for epilepsy. Epilepsia 24:531–538.
Gonsalves, S. F., Twitchell, B., Harbaugh, R. E., and Krogsgaard-Larsen, P., and Schousboe, A. 1989. Anticonvulsant activity of intracerebroventricularly administered glial GABA uptake inhibitors and other GABAmimetics in chemical seizure models. Epilepsy Res. 4:34–41.
Gonsalves, S. F., Twitchell, B., Harbaugh, R. E., Krogsgaard-Larsen, P., and Schousboe, A. 1989. Anticonvulsant activity of the glial GABA uptake inhibitor, THAO, in chemical seizures. Eur. J. Pharmacol. 168:265–268.
Corey, J. L., Davidson, N., Lester, H. A., Brecha, N., and Quick, M. W. 1994. Protein kinase C modulates the activity of a cloned γ-aminobutyric acid transporter expressed in Xenopus oocytes via regulated subcellular distribution of the transporter J. Biol. Chem. 269:14759–14767.
Gomeza, J., Gimenez, C., and Zafra, F. 1994. Cellular distribution and regulation by cAMP of the GABA transporter (GAT-1) mRNA. Molec. Brain Res. 21:150–156.
Osawa, I., Saito, N., Koga, T., and Tanaka, C. 1994. Phorbol ester-induced inhibition of GABA uptake by synaptosomes and by Xenopus oocytes expressing GABA transporter (GAT-1). Neurosci. Res. 19:287–293.
Tian, Y., Kapatos, G., Granneman, J. G., and Bannon, M. J. 1994. Dopamine and γ-aminobutyric acid transporters: Differential regulation by agents that promote phosphorylation. Neurosci. Lett. 173:143–146.
Nissen, J., Schousboe, A., Halkier, T., and Schousboe, I. 1992. Purification and characterization of an astrocyte GABA-carrier inducing protein (GABA-CIP) released from cerebellar granule cells. Glia 6:236–243.
Bernstein, E. M. and Quick, M. W. 1999. Regulation of gamma-aminobutyric acid (GABA) transporters by extracellular GABA. J. Biol. Chem. 274:889–895.
Quick, M. W. 2002. Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner. Proc. Natl. Acad. Sci. USA 99:5686–5691.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schousboe, A. Role of Astrocytes in the Maintenance and Modulation of Glutamatergic and GABAergic Neurotransmission. Neurochem Res 28, 347–352 (2003). https://doi.org/10.1023/A:1022397704922
Issue Date:
DOI: https://doi.org/10.1023/A:1022397704922