 |
|
Glutamate Transporters in Neurologic Disease
Nicholas J. Maragakis, MD;
Jeffrey D. Rothstein, MD, PhD
Arch Neurol. 2001;58:365-370.
INTRODUCTION
Glutamate is the primary excitatory amino acid neurotransmitter in the
human brain. It is important in synaptic plasticity, learning, and development.
Its activity at the synaptic cleft is carefully balanced by receptor inactivation
and glutamate reuptake. When this balance is upset, excess glutamate can itself
become neurotoxic.
The neurotoxic properties of glutamate were first demonstrated in 1957
by Lucas and Newhouse,1 who showed that systemic
administration of glutamate to infant mice caused retinal degeneration. Over
the last 4 decades, a direct correlation between the neuroexcitatory and neurotoxic
properties of glutamate has been linked to activation of excitatory amino
acid receptors.2, 3, 4, 5
This overactivation leads to an enzymatic cascade of events ultimately resulting
in cell death.
Regulation of synaptic transmission and glutamate levels in the synaptic
cleft is performed by glutamate transporters. Glutamate transport is a sodium-
and potassium-coupled process that is capable of concentrating intracellular
glutamate up to 10 000-fold compared with the extracellular space.6, 7 These transporters are located throughout
the human central nervous system as well as other tissues. Recent physiologic
studies provide evidence that glutamate transporters keep synaptic concentrations
of glutamate low enough to prevent receptor desensitization and/or excitotoxicity.
New insights into the biology of these transporters suggest that their dysfunction
may contribute to neurologic disease.
HUMAN GLUTAMATE TRANSPORTERS
Both neurons and astroglia are capable of high-affinity, sodium-dependent
glutamate transport.8 To date, 5 high-affinity,
sodium-dependent glutamate transporters have been cloned from mammalian and
human tissue: astrocyte-specific glutamate transporter (GLAST [excitatory
amino acid transporter 1 (EAAT1)]), glutamate transporter 1 (GLT-1 [excitatory
amino acid transporter 2 (EAAT2)]), excitatory amino acid carrier 1 (EAAC1
[excitatory amino acid transporter 3 (EAAT3)]), excitatory amino acid transporter
4 (EAAT4), and excitatory amino acid transporter 5 (EAAT5) (Table 1).9, 10, 11, 12, 13, 14
|
|
|
|
Distribution of Mammalian Glutamate Transporters and Their Human Homologues*
|
|
|
Immunohistochemical studies have revealed that EAAT1 and EAAT2 are localized
primarily in astrocytes, while EAAT3 and EAAT4 are distributed in neuronal
membranes. Detailed immunogold studies have further delineated the localization
of glutamate transporters to certain subcellular compartments. The neuronal
transporters EAAT3 and EAAT4 appear to be localized to plasma membranes in
a perisynaptic distribution. The greatest density of these transporter proteins
appears to be at the edge of postsynaptic densities, rather than within the
synaptic cleft. To date, most immunolocalization studies have further indicated
that the neuronal transporters are localized in a somatodendritic fashion
on postsynaptic spines and somas. They are rarely found presynaptically. In
fact, to date, the only localization of glutamate transporters presynaptically
has been on presynaptic inhibitory  -aminobutyric acid (GABA) terminals.15
In a similar fashion, the astroglial glutamate transporters also have
a polarized distribution. Both EAAT1 and EAAT2 are localized to astroglial
membranes that immediately oppose synaptic cleft regions of the neuropil (Figure 1).16
In mammalian studies, it has been demonstrated that EAAT1 is highly expressed
in the molecular layer of the cerebellum and moderates activity in the hippocampus,
superior colliculus, and substantia gelatinosa of the spinal cord. In contrast,
EAAT2 expression is generally high throughout all brain regions and the spinal
cord but is largely absent from white matter tracts; EAAT3 is selectively
enriched in neurons of the hippocampus, cerebellum, and basal ganglia; EAAT4
is largely confined to the soma and dendrites of the Purkinje cells of the
cerebellum; EAAT5 is located in retinal ganglion cells (Table 1).
|
|
|
Figure 1. Cellular localization of glutamate
(Glu) transporter subtypes: EAAT1 and EAAT2 are found in the perisynaptic
region of astroglial membranes; EAAT3 and EAAT4 are localized to neuronal
membranes. mGluR indicates metabotropic glutamate receptor; K, potassium;
Na, sodium; Cl, chlorine; NMDA, N-methyl-D-aspartate; and AMPA,  -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic
acid. See Table 1 footnotes for
an explanation of EAAT1 through EAAT4.
|
|
|
Thus, the anatomic analysis of the molecular subtypes of glutamate transporters
suggests that glutamate inactivation may be either postsynaptic or on astroglial
membranes. In fact, in the hippocampus, a region of intense glutamatergic
innervation, there is little evidence for presynaptic or postsynaptic inactivation
by neuronal transporters. Rather, all available data suggest that astroglial
transporters are the predominant physiologic pathway for synaptic inactivation
of glutamate in the forebrain.
NEUROSCIENTIFIC STUDY OF GLUTAMATE TRANSPORTER DYSFUNCTION
How does glutamate transporter dysfunction lead to neurotoxic effects
and subsequent neurologic sequelae? The relationship between loss of glutamate
transporters and enhancement of extracellular glutamate levels with subsequent
neurotoxic effects has been well established.
Knockout mice deficient in the glutamate transporter subtypes have been
developed. They yield a variety of phenotypes, including seizures, loss of
motor coordination, and disturbances in amino acid metabolism.17, 18
The knockout-mouse model allows for the study of glutamate and its transporters
throughout the development of the mammalian brain.
A second method in examining the effects of loss of glutamate transport
is the use of antisense oligonucleotides to reduce the number of glutamate
transporters in adult animals. Antisense oligonucleotides are believed to
exhibit their effect by binding to the target messenger RNA (mRNA) and preventing
its translation into the target protein. The infusion of these molecules over
days to weeks simulates the chronic loss of transporters that may occur in
neurodegenerative disorders. Reduction in various subtypes of glutamate transporters
has led to models of amyotrophic lateral sclerosis (ALS) and epilepsy by increasing
glutamate in the synaptic cleft and producing subsequent neurotoxic effects.
Cell culture systems have provided new evidence that supports the participation
of reactive oxygen species (peroxynitrite, among others) in inhibiting glutamate
transporter activity.19 This inhibition leads
to increased extracellular glutamate, which, through the activation of glutamate
receptors, generates a cascade of enzymatic steps that further enhance the
formation of reactive oxygen species.
Finally, models of hypoxia have been generated that show that depletion
of adenosine triphosphate levels leads to the rundown of glutamate transport
and actually leads to reversed uptake and the extrusion of glutamate into
the synaptic cleft. This process further induces glutamate neurotoxic effects
and may play a role in enhancing cell death (Figure 2).
|
|
|
|
Figure 2. Under normal conditions, glutamate
(Glu) released into the synaptic cleft is removed (thick solid arrows at left)
by sodium (Na)-dependent neuronal and astroglial Glu transporters (red and
yellow ovals). Increased Glu at the synapse can result from the reversal of
Glu transport (dashed arrows) under conditions of adenosine triphosphate depletion
(ischemia). Truncated Glu transporters (incomplete ovals) may interact with
full-length transporters to be sequestered within the cell or trafficked to
the membrane, where they function ineffectively. Reactive oxygen species (ONOO-, OH-) generated by a variety of conditions
may damage transporters (withered oval), with a resultant reduction in Glu
transport. K indicates potassium; Na, sodium; Cl, chlorine; NMDA, N-methyl-D-aspartate; ATP, adenosine triphosphatase; and AMPA, -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic
acid.
|
|
|
Whether loss of glutamate transporter function is the primary insult
or part of a cascade leading to neuronal death, it is becoming increasingly
clear that glutamate transporters play a role in neurologic disease.
GLUTAMATE TRANSPORT AND HUMAN DISEASE
Amyotrophic Lateral Sclerosis
Multiple mechanisms have been postulated to cause motor neuron degeneration
in sporadic and familial forms of ALS, including excitotoxic effects, oxidative
injury, cytoskeletal abnormalities, and autoimmunity. It is likely that multiple
primary insults result in the common phenotype of ALS. Evidence for glutamate
contributing to motor neuron degeneration in ALS initially came from several
studies that suggested that cerebrospinal fluid glutamate levels may be elevated
in patients with sporadic ALS.20, 21
These earlier studies reported that motor cortex and spinal cord tissue glutamate
levels were decreased 30% to 45% in patients with ALS. These alterations in
extracellular and tissue glutamate may in fact reflect alterations in glutamate
transport. This hypothesis was subsequently evaluated and confirmed through
the use of membrane preparations of postmortem tissue from ALS patients and
controls. In those studies, a significant loss of high-affinity, sodium-dependent
glutamate transport was found in ALS.22 Detailed
studies were performed to examine molecular subtypes of glutamate transport
in ALS. These revealed that up to 60% to 70% of patients with sporadic ALS
have a 30% to 90% loss of the EAAT2 protein, in both motor cortex and spinal
cord.23 The loss of EAAT2 appears to be specific
to these regions in most but not all patients. This loss of EAAT2 protein
cannot be attributed to cell death since there is no significant astroglial
loss in ALS.
Parallel with human studies, a number of laboratories have been investigating
the biology of the EAAT2 protein. Functional studies have determined that
the EAAT2 transporter is the most abundant glutamate transporter in the brain,
both at the protein level and functionally. Up to 95% of all tissue glutamate
transport appears to be through the EAAT2 glutamate transporter.17
What is the relevance of a loss of EAAT2? Both in vitro and in vivo
studies have documented that antisense knockdown or pharmacologic inhibition
of a glutamate transporter leads to neuronal degeneration, especially of the
motor neurons. In adult animals, antisense knockdown of EAAT2, analogous to
an adult-onset loss of EAAT2 in ALS, leads to progressive paralysis in motor
neuron degeneration.24 Thus, the loss of EAAT2
protein is sufficient to induce a phenotype of motor neuron degeneration.
What could cause the loss of an astroglial glutamate transporter in
a regional manner in sporadic ALS? Two possible mechanisms for loss of glutamate
transporter proteins in ALS have been suggested. First, studies in ALS have
revealed the presence of truncated RNA species in patients with sporadic ALS.
Detailed analyses have revealed that ALS is associated with a large increase
in multiple aberrant RNA species that code for truncated versions of the EAAT2
protein. Although 1 or 2 of these species can occasionally be seen in control
specimens, ALS is unique in both the abundance, using vigorous quantitative
methods to assess these truncated RNA species, and the large number of different
truncated RNA species in individual patients.25
Studies of some of these truncated species indicate that they have a dominant-negative
effect on the EAAT2 protein and provide a mechanism for explaining a loss
of EAAT2 protein in patients.
Second, evidence suggesting a link between free radical formation and
glutamate transporter dysfunction comes from a mouse model of ALS. Mutations
of superoxide dismutase (SOD1) have been found in
approximately 10% of patients with familial ALS.26
Transgenic mice overexpressing mutant SOD1 genes
display a slowly progressive motor neuron disease resembling ALS.27 The mechanism for the neurotoxic effects associated
with mutant SOD1 is not yet known, but evidence supports
the gain of a toxic property.28, 29, 30
In addition, recent studies have documented that mutant SOD1 by itself can induce oxidative damage to the EAAT2 protein that
could also provide an alternate means for loss of glutamate transport in ALS
patients.31 Regardless of the mechanism, the
loss of EAAT2 glutamate transporter may contribute to a reduction in glutamate
uptake with subsequent overstimulation of glutamate receptors, resulting in
neurotoxic effects.
As described above, glutamate transporters may be a target for these
toxic effects. In fact, recent studies of SOD1 transgenic
mice show a marked loss of GLT1 (EAAT2) in the spinal cord as well as a loss
of functional glutamate transport.32 Thus,
the loss of glutamate transport is seen both in familial models of ALS and
in sporadic disease.
Alzheimer Disease
The neurodegeneration in AD is characterized by synaptic and neuronal
loss with plaque and tangle formation. Abnormal expression or processing of
growth-associated proteins in the central nervous system may play a role in
the process, leading to damage and neurodegeneration. Amyloid precursor protein
has been implicated as being important in the pathogenesis of AD. Recently,
it has been demonstrated that abnormal processing of amyloid precursor protein
may be associated with the deficient functioning of the glutamate transporter
system. In fact, a fragment of ß-amyloid (Aß), the central constituent
of neuritic plaques in AD, inhibited tritium-labeled glutamate uptake in cultured
astrocytes. Since reactive oxygen species are mediators of Aß toxic effects
and uptake inhibition by Aß was prevented by antioxidants, it is conceivable
that, among other effects, Aß produces glutamate transporter oxidation
and dysfunction.33
Stroke/Ischemia
Aberrant function of glutamate transport plays an essential role in
the excitotoxic neurodegeneration that occurs in models of cerebral ischemia.
As mentioned in the introduction, there is a tenfold higher concentration
of glutamate within cells compared with the outside environment. The energy
and ion gradient necessary to maintain this state fail under ischemic conditions.
In fact, numerous in vitro studies have documented the actual reversal of
glutamate transporter: glutamate that runs down its gradient from within cells
to swamp the extracellular environment with large amounts of intracellular
glutamate.34, 35, 36
Changes in glutamate transporter expression are seen with cerebral ischemia
in animal models and human tissue. Astrocyte-specific glutamate transporter
expression was increased in the penumbra 72 hours following ischemia in an
animal model. This suggests that a compensatory increase in the activity of
glutamate transporters may accompany pathological changes after ischemic injury.37 The paucity of GLAST and GLT1 in specific regions
of the hippocampus may account for the vulnerability of these neurons to an
ischemic insult.38
Transient hypoxic-ischemic injury in a neonatal pig model demonstrates
reduced levels of GLT1 and EAAC1 at 24 hours of recovery. Thus, astroglial
and neuronal injury were found to occur rapidly in the newborn striatum, with
early gliodegeneration and glutamate transporter abnormalities contributing
to neurodegeneration.39
Selective cell vulnerability to neonatal hypoxia-ischemia may be attributed
to loss of glutamate transporter subtypes. Changes in GLAST and EAAT4 (a Purkinje
cell–specific transporter) in the cerebellum of hypoxic human neonates,
examined postmortem, may account for the well-described vulnerability of Purkinje
cells to hypoxic injury.40
While the regulation of the different transporter subtypes in varying
anatomic regions and ischemic zones is still being studied, these changes
are in response to and a result of neurotoxic effects.
Epilepsy
The family of glutamate transporter proteins may also be participants
in certain models of epilepsy, although their role may be dependent more on
their participation in the central nervous system metabolism than on their
role as regulators of external glutamate concentrations. In knockout mice,
a reduction in the glutamate transporter GLT1 results in lethal spontaneous
seizures. By 6 weeks of age, 50% of animals die. Pathologically, some of the
mice that lack the GLT1 transporter show destruction of neurons in the hippocampus,
a region found to be important in the generation of seizure disorders.17 Interestingly, developmental studies indicate that
this time point is critical for the development of excitatory synapses. The
loss of a predominant glutamate transporter in the neonatal brain, GLT1, therefore
may be critical for normal synaptogenesis and prevention of seizures. In that
regard, it is interesting that in adult animals, the loss of GLT1 leads not
to seizures but, as described above, motor neuron degeneration. Thus, alterations
in transporter expression may have pathophysiologic consequences for the cell
types in which they are expressed, their ultrastructural localization, and
the developmental timing at which insults occur. Interestingly, GLAST and
EAAC1 knockout mice, while not normal, do not develop seizures.
In acquired models of epilepsy in which seizures are induced using a
variety of pharmacological models, the data are somewhat conflicting. In a
study of mRNA and protein expression using fully kindled rats, few changes
in GLT or GLAST were found in the hippocampus.41
Conversely, when the glutamate receptor agonist kainate was used to induce
seizures, EAAC1 mRNA and protein levels were decreased in the rat hippocampus,
GLT1 mRNA and protein levels were increased, and GLAST mRNA levels were increased.42, 43
Recent experimental studies have provided a new means by which glutamate
transporters may contribute to epilepsy. Infusing antisense oligonucleotides
into the ventricles of adult rats with the molecular knockdown of EAAC1, a
highly expressed hippocampal transporter, can produce episodic seizures in
these animals.24 Initial studies suggest that
this effect occurs not through alterations of an extracellular glutamate,
but rather through perturbations of the neurotransmitter GABA. The EAAC1 transporter
is highly localized to GABA presynaptic terminals, and preliminary studies
suggest that its dysfunction can alter neurotransmitter GABA metabolism (unpublished
results from our laboratory). This alteration results in a loss of presynaptic
release of GABA, diminishing inhibition. A disturbance of this metabolic function
of glutamate transporters could underlie some pathophysiologic pathways of
epilepsy.
In patients undergoing anterior temporal lobectomy for refractory seizures,
brain tissue from the anterior temporal lobe did not reveal changes in the
level of expression of the glutamate transporters EAAT1 and EAAT2.44 In human studies of hippocampal sclerosis, however,
EAAT2 and EAAT3 levels are increased in areas where neurons are spared and
reduced in regions of neuronal cell loss.45
Taken together, these data suggest that alterations in glutamate transporters
in both human tissue and animal models may play a role in the generation and
propagation of ictal activity. Determining whether these changes are the primary
cause of induction of seizures or a compensatory response to neuronal injury
requires further study.
APPLICATIONS FOR DIAGNOSIS
Currently, the World Federation of Neurology criteria are used to establish
a diagnosis of ALS.46 These criteria are based
upon history and physical findings suggesting loss of upper and lower motor
neurons and electrophysiologic evidence of denervation. Unfortunately, the
diagnosis is often not established until late in the disease. New approaches
to support the diagnosis are therefore welcome.
Lin et al25 detected EAAT2 mRNA splice
mutants in the cerebrospinal fluid of 66% of patients with sporadic ALS, but
none in patients with nonneurologic disease or in controls with other diseases.
Importantly, these splice mutants were also detectable early in the course
of the disease. Although currently reliable qualitative and quantitative polymerase
chain reaction methods might be difficult to perform in clinical laboratories,
the collection of cerebrospinal fluid could be an adjunct to the current methods
of diagnosis in the future. The identification of markers contributing to
disease activity by conventional lumbar puncture may eventually lead to earlier
diagnosis and institution of treatment for this devastating disease.
COMMENT
Glutamate neurotoxicity has long been known to contribute to the pathogenesis
of neurologic disorders such as stroke, epilepsy, and ALS. The finding that
glutamate transporter dysfunction plays a role in these disorders is a more
recent discovery. Given that glutamate is ubiquitous in the central nervous
system, glutamate transporter dysfunction may play a role in other neurologic
disorders as well.
At the present time, several drugs used to treat neurologic disorders
have activity at the glutamatergic synapse. Glutamate receptor antagonists
have been tried in stroke in an attempt to limit the size and severity of
ischemic insults. Riluzole is currently approved for use in the treatment
of ALS and is believed to act by preventing the release of glutamate.47 The antiepileptic drug topiramate acts as an antagonist
of the AMPA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate
subtype of the glutamate receptor.48
Recently, a number of proteins have been identified that can modulate
glutamate transporters.49, 50 These
proteins appear either to potently stimulate or to inhibit glutamate transporter
subtypes. Future manipulation of these proteins may also provide novel therapeutic
means to regulate glutamate transport and afford therapeutic benefit.
Given what we have learned from the therapeutic applications of compounds
active at glutamatergic synapses, manipulation of glutamate transporters may
also prove promising. Future directions could include the development of glutamate
transporter agonists to increase glutamate uptake from the synaptic cleft.
The use of gene therapy to deliver genes of interest to particular cell
types is a rapidly expanding field. Gene therapy may be implemented to overexpress
glutamate transporters in target cells. Glutamate transport from the extracellular
space could be facilitated by increasing the number of glutamate transporters
in neurons and glia.
The biology of free radical formation and its relationship to disease
has garnered a great deal of attention recently. This has led to the pharmaceutical
use of antioxidants to treat a host of different disorders. Antioxidants may
be of use in preventing damage to glutamate transporters, offering an exciting
approach to preventing glutamate accumulation in the synapse.
The study of these transporters as they relate to neurologic disease
in humans is in its infancy. Understanding their biology will be critical
in developing strategies for manipulating them in the future.
AUTHOR INFORMATION
Accepted for publication April 26, 2000.
From the Department of Neurology, Johns Hopkins University, Baltimore,
Md.
Corresponding author and reprints: Jeffrey D. Rothstein, Department
of Neurology, Johns Hopkins University, Meyer 6-109, 600 N Wolfe St, Baltimore,
MD 21287 (e-mail: jrothste{at}jhmi.edu).
REFERENCES
| |
1. Lucas DR, Newhouse JP. The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch Ophthalmol. 1957;58:193-201.
FREE FULL TEXT
2. Olney JW, Ho OL. Brain damage in infant mice following oral intake of glutamate, aspartate
or cysteine. Nature. 1970;227:609-611.
PUBMED
3. Olney JW. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus:
an electron microscopic study. J Neuropathol Exp Neurol. 1971;30:75-90.
ISI
| PUBMED
4. Olney JW. The toxic effects of glutamate and related compounds in the retina
and the brain. Retina. 1982;2:341-359.
FULL TEXT
|
ISI
| PUBMED
5. Olney JW. Brain lesions, obesity, and other disturbances in mice treated with
monosodium glutamate. Science. 1969;164:719-721.
FREE FULL TEXT
6. Kanner BI, Schuldiner S. Mechanism of transport and storage of neurotransmitters [review]. CRC Crit Rev Biochem. 1987;22:1-38.
ISI
| PUBMED
7. Nicholls D, Attwell D. The release and uptake of excitatory amino acids [review]. Trends Pharmacol Sci. 1990;11:462-468.
FULL TEXT
| PUBMED
8. Hertz L. Functional interactions between neurons and astrocytes, I: turnover
and metabolism of putative amino acid transmitters [review]. Prog Neurobiol. 1979;13:277-323.
FULL TEXT
|
ISI
| PUBMED
9. Pines G, Danbolt NC, Bjoras M, et al. Cloning and expression of a rat brain L-glutamate transporter Nature. 1992;360:464-467. [published erratum appears in Nature. 1992;360:768].
PUBMED
10. Kanai Y, Hediger MA. Primary structure and functional characterization of a high-affinity
glutamate transporter. Nature. 1992;360:467-471.
FULL TEXT
| PUBMED
11. Storck T, Schulte S, Hofmann K, Stoffel W. Structure, expression, and functional analysis of a Na(+)-dependent
glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci U S A. 1992;89:10955-10959.
FREE FULL TEXT
12. Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG. Functional comparisons of three glutamate transporter subtypes cloned
from human motor cortex. J Neurosci. 1994;14:5559-5569.
ABSTRACT
13. Fairman WA, Vandenberg RJ, Arriza JL, Kavanaugh MP, Amara SG. An excitatory amino-acid transporter with properties of a ligand-gated
chloride channel. Nature. 1995;375:599-603.
FULL TEXT
| PUBMED
14. Arriza JL, Eliasof S, Kavanaugh MP, Amara SG. Excitatory amino acid transporter 5, a retinal glutamate transporter
coupled to a chloride conductance. Proc Natl Acad Sci U S A. 1997;94:4155-4160.
FREE FULL TEXT
15. Furuta A, Martin LJ, Lin CLG, Dykes-Hoberg M, Rothstein JD. Cellular and synaptic localization of the neuronal glutamate transporters
excitatory amino acid transporter 3 and 4. Neuroscience. 1997;81:1031-1042.
FULL TEXT
|
ISI
| PUBMED
16. McDermott RH, Butler M. Uptake of glutamate, not glutamine synthetase, regulates adaptation
of mammalian cells to glutamine-free medium. J Cell Sci. 1993;104:51-58.
ABSTRACT
17. Tanaka K, Watase K, Mabe T, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate
transporter GLT-1. Science. 1997;276: 1699-1702.
18. Peghini P, Janzen J, Stoffel W. Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria
and behavioral abnormalities but no neurodegeneration. EMBO J. 1997;16:3822-3832.
FULL TEXT
|
ISI
| PUBMED
19. Trotti D, Rossi D, Gjesdal O, et al. Peroxynitrite inhibits glutamate transporter subtypes. J Biol Chem. 1996;271:5976-5979.
FREE FULL TEXT
20. Rothstein JD, Tsai G, Kuncl RW, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol. 1990;28:18-25.
FULL TEXT
|
ISI
| PUBMED
21. Rothstein JD, Kuncl R, Chaudry V, et al. Excitatory amino acids in amyotrophic lateral sclerosis: an update
[letter]. Ann Neurol. 1991;30:224-225.
FULL TEXT
|
ISI
| PUBMED
22. Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic
lateral sclerosis. N Engl J Med. 1992;326:1464-1468.
ABSTRACT
23. Bristol LA, Rothstein JD. Glutamate transporter gene expression in amyotrophic lateral sclerosis
motor cortex. Ann Neurol. 1996;39:676-679.
FULL TEXT
|
ISI
| PUBMED
24. Rothstein JD, Dykes-Hoberg M, Pardo CA, et al. Knockout of glutamate transporters reveals a major role for astroglial
transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16:675-686.
FULL TEXT
|
ISI
| PUBMED
25. Lin CL, Bristol LA, Jin L, et al. Aberrant RNA processing in a neurodegenerative disease: the cause for
absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron. 1998;20:589-602.
FULL TEXT
|
ISI
| PUBMED
26. Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial
amyotrophic lateral sclerosis. Nature. 1993;362:59-62.
FULL TEXT
| PUBMED
27. Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide
dismutase mutation. Science. 1994;264:1772-1775.
FREE FULL TEXT
28. Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW. Transgenic mice expressing an altered murine superoxide dismutase gene
provide an animal model of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 1995;92:689-693.
FREE FULL TEXT
29. Zhang Y, Pines G, Kanner BI. Histidine 326 is critical for the function of GLT-1, a (Na+ + K+)-coupled
glutamate transporter from rat brain. J Biol Chem. 1994;269:19573-19577.
FREE FULL TEXT
30. Reaume AG, Elliott JL, Hoffman EK, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop
normally but exhibit enhanced cell death after axonal injury. Nat Genet. 1996;13:43-47.
FULL TEXT
|
ISI
| PUBMED
31. Trotti D, Rolfs A, Danbolt NC, Brown RH Jr, Hediger MA. SOD1 mutants linked to amyotrophic lateral
sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci. 1999;2:427-433.
FULL TEXT
|
ISI
| PUBMED
32. Bruijn LI, Becher MW, Lee MK, et al. ALS-linked SOD1 mutant G85R mediates damage
to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997;18:327-338.
FULL TEXT
|
ISI
| PUBMED
33. Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L. Deficient glutamate transport is associated with neurodegeneration
in Alzheimer's disease. Ann Neurol. 1996;40:759-766.
FULL TEXT
|
ISI
| PUBMED
34. Billups B, Attwell D. Modulation of non-vesicular glutamate release by pH. Nature. 1996;379:171-174.
FULL TEXT
| PUBMED
35. Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic
glutamate uptake. Nature. 1990;348:443-446.
FULL TEXT
| PUBMED
36. Storm-Mathisen J, Danbolt NC, Rothe F, et al. Ultrastructural immunocytochemical observations on the localization,
metabolism and transport of glutamate in normal and ischemic brain tissue
[review]. Prog Brain Res. 1992;94:225-241.
ISI
| PUBMED
37. Kalra S, Arnold DL, Cashman NR. Biological markers in the diagnosis and treatment of ALS [review]. J Neurol Sci. 1999;165(suppl 1):S27-S32.
38. Fujita H, Sato K, Wen TC, Peng Y, Sakanaka M. Differential expressions of glycine transporter 1 and three glutamate
transporter mRNA in the hippocampus of gerbils with transient forebrain ischemia. J Cereb Blood Flow Metab. 1999;19:604-615.
FULL TEXT
|
ISI
| PUBMED
39. Martin LJ, Brambrink AM, Lehmann C, et al. Hypoxia-ischemia causes abnormalities in glutamate transporters and
death of astroglia and neurons in newborn striatum. Ann Neurol. 1997;42:335-348.
FULL TEXT
|
ISI
| PUBMED
40. Inage YW, Itoh M, Wada K, Takashima S. Expression of two glutamate transporters, GLAST and EAAT4, in the human
cerebellum: their correlation in development and neonatal hypoxic-ischemic
damage. J Neuropathol Exp Neurol. 1998;57:554-562.
ISI
| PUBMED
41. Akbar MT, Torp R, Danbolt NC, Levy LM, Meldrum BS, Ottersen OP. Expression of glial glutamate transporters GLT-1 and GLAST is unchanged
in the hippocampus in fully kindled rats. Neuroscience. 1997;78:351-359.
FULL TEXT
|
ISI
| PUBMED
42. Nonaka M, Kohmura E, Yamashita T, et al. Increased transcription of glutamate-aspartate transporter (GLAST/GluT-1)
mRNA following kainic acid-induced limbic seizure. Brain Res Mol Brain Res. 1998;55:54-60.
PUBMED
43. Simantov R, Crispino M, Hoe W, et al. Changes in expression of neuronal and glial glutamate transporters
in rat hippocampus following kainate-induced seizure activity. Brain Res Mol Brain Res. 1999;65:112-123.
PUBMED
44. Tessler S, Danbolt NC, Faull RLM, Storm-Mathisen J, Emson PC. Expression of the glutamate transporters in human temporal lobe epilepsy. Neuroscience. 1999;88:1083-1091.
FULL TEXT
|
ISI
| PUBMED
45. Niebroj-Dobosz I, Janik P. Amino acids acting as transmitters in amyotrophic lateral sclerosis
(ALS). Acta Neurol Scand. 1999;100:6-11.
ISI
| PUBMED
46. Brooks BR for the Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis
of the World Federation of Neurology Research Group on Neuromuscular Diseases
and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop
contributors. El Escorial World Federation of Neurology criteria for the diagnosis
of amyotrophic lateral sclerosis. J Neurol Sci. 1994;124(suppl):96-107.
47. Martin D, Thompson MA, Nadler JV. The neuroprotective agent riluzole inhibits release of glutamate and
aspartate from slices of hippocampal area CA1. Eur J Pharmacol. 1993;250:473-476.
FULL TEXT
|
ISI
| PUBMED
48. Shank RP, Gardocki JF, Vaught JL, et al. Topiramate: preclinical evaluation of structurally novel anticonvulsant. Epilepsia. 1994;35:450-460.
FULL TEXT
|
ISI
| PUBMED
49. Jackson M, Jin L, Dykes-Hoberg M, et al. Activation of excitatory amino acid transporter 4 (EAAT4) by two novel
interacting proteins. Abstract presented at: 29th Annual Meeting of the Society for Neuroscience;
October 24, 1999; Miami, Fla. Abstract No. 170.3.
50. Lin CLG, Orlov I, Dykes-Hoberg M, Jin L, Rothstein J. Allosteric modulation of neuronal glutamate transporter EAAC1 by a
novel associated protein GTRAP-18. Abstract presented at: 29th Annual Meeting of the Society for Neuroscience;
October 24, 1999; Miami, Fla. Abstract No. 170.4.
SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLE
Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 2001;58(3):523-525.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Beneficial Effects of Ceftriaxone Against Pentylenetetrazole-Evoked Convulsions
Jelenkovic et al.
Exp. Biol. Med. 2008;233:1389-1394.
ABSTRACT
| FULL TEXT
Selective defect of in vivo glycolysis in early Huntington's disease striatum
Powers et al.
Proc. Natl. Acad. Sci. USA 2007;104:2945-2949.
ABSTRACT
| FULL TEXT
Is Huntington's a Glutamine Storage Disease?
Brusilow
Neuroscientist 2006;12:300-304.
ABSTRACT
Impaired Glutamate Transport in a Mouse Model of Tau Pathology in Astrocytes
Dabir et al.
J. Neurosci. 2006;26:644-654.
ABSTRACT
| FULL TEXT
Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity
Shin et al.
JCB 2005;171:1001-1012.
ABSTRACT
| FULL TEXT
Antibiotics that protect the brain
Secko
CMAJ 2005;172:467-468.
FULL TEXT
Rapid Trafficking of the Neuronal Glutamate Transporter, EAAC1: EVIDENCE FOR DISTINCT TRAFFICKING PATHWAYS DIFFERENTIALLY REGULATED BY PROTEIN KINASE C AND PLATELET-DERIVED GROWTH FACTOR
Fournier et al.
J. Biol. Chem. 2004;279:34505-34513.
ABSTRACT
| FULL TEXT
Cortical selective vulnerability in motor neuron disease: a morphometric study
Maekawa et al.
Brain 2004;127:1237-1251.
ABSTRACT
| FULL TEXT
In Vitro Ischemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-{alpha} Pathway
Romera et al.
J. Neurosci. 2004;24:1350-1357.
ABSTRACT
| FULL TEXT
Functional characterization of a glutamate/aspartate transporter from the mosquito Aedes aegypti
Umesh et al.
J. Exp. Biol. 2003;206:2241-2255.
ABSTRACT
| FULL TEXT
Methylmercury Increases Glutamate Release from Brain Synaptosomes and Glutamate Uptake by Cortical Slices from Suckling Rat Pups: Modulatory Effect of Ebselen
Farina et al.
Toxicol Sci 2003;73:135-140.
ABSTRACT
| FULL TEXT
Retinal Glutamate Transporter Changes in Experimental Glaucoma and after Optic Nerve Transection in The Rat
Martin et al.
IOVS 2002;43:2236-2243.
ABSTRACT
| FULL TEXT
Mechanisms of neurodegeneration in amyotrophic lateral sclerosis
Cluskey and Ramsden
Mol. Pathol. 2001;54:386-392.
ABSTRACT
| FULL TEXT
Postmortem brain abnormalities of the glutamate neurotransmitter system in autism
Purcell et al.
Neurology 2001;57:1618-1628.
ABSTRACT
| FULL TEXT
|
