Fw: about essential amino acid glutamate which is found in NV

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Glutamate Transporters in Neurologic Disease

J. Maragakis, MD; D. Rothstein, MD, PhD

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 {gamma}-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,

{alpha}-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).

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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,

{alpha}-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

({alpha}-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

From the Department of Neurology, s Hopkins University, Baltimore, Md.

Corresponding author and reprints: D. Rothstein, Department of

Neurology, s Hopkins University, Meyer 6-109, 600 N Wolfe St, Baltimore, MD

21287 (e-mail: jrothste@...).

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SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD

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