Elsevier

Neurochemistry International

Volume 51, Issues 6–7, November–December 2007, Pages 333-355
Neurochemistry International

Review
The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention

https://doi.org/10.1016/j.neuint.2007.03.012Get rights and content

Abstract

Extracellular concentrations of the predominant excitatory neurotransmitter, glutamate, and related excitatory amino acids are maintained at relatively low levels to ensure an appropriate signal-to-noise ratio and to prevent excessive activation of glutamate receptors that can result in cell death. The latter phenomenon is known as ‘excitotoxicity’ and has been associated with a wide range of acute and chronic neurodegenerative disorders, as well as disorders that result in the loss of non-neural cells such as oligodendroglia in multiple sclerosis. Unfortunately clinical trials with glutamate receptor antagonists that would logically seem to prevent the effects of excessive receptor activation have been associated with untoward side effects or little clinical benefit. In the mammalian CNS, the extracellular concentrations of glutamate are controlled by two types of transporters; these include a family of Na+-dependent transporters and a cystine–glutamate exchange process, referred to as system Xc. In this review, we will focus primarily on the Na+-dependent transporters. A brief introduction to glutamate as a neurotransmitter will be followed by an overview of the properties of these transporters, including a summary of the presumed physiologic mechanisms that regulate these transporters. Many studies have provided compelling evidence that impairing the function of these transporters can increase the sensitivity of tissue to deleterious effects of aberrant activation of glutamate receptors. Over the last decade, it has become clear that many neurodegenerative disorders are associated with a change in localization and/or expression of some of the subtypes of these transporters. This would suggest that therapies directed toward enhancing transporter expression might be beneficial. However, there is also evidence that glutamate transporters might increase the susceptibility of tissue to the consequences of insults that result in a collapse of the electrochemical gradients required for normal function such as stroke. In spite of the potential adverse effects of upregulation of glutamate transporters, there is recent evidence that upregulation of one of the glutamate transporters, GLT-1 (also called EAAT2), with β-lactam antibiotics attenuates the damage observed in models of both acute and chronic neurodegenerative disorders. While it seems somewhat unlikely that antibiotics specifically target GLT-1 expression, these studies identify a potential strategy to limit excitotoxicity. If successful, this type of approach could have widespread utility given the large number of neurodegenerative diseases associated with decreases in transporter expression and excitotoxicity. However, given the massive effort directed at developing glutamate receptor agents during the 1990s and the relatively modest advances to date, one wonders if we will maintain the patience needed to carefully understand the glutamatergic system so that it will be successfully targeted in the future.

Introduction

Glutamate is the predominant excitatory neurotransmitter in the mammalian CNS. Glutamate activates a family of ligand gated ion channels that were originally named for exogenous agonists that are selective for each subtype and include α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate, and N-methyl-d-aspartate (NMDA). Each of these receptors are multimeric assemblies of one or more subunits, and there are considerable numbers of variants of the subunits related to either alternate splicing of the RNA transcripts or editing of the RNA that results in changes in a single base and a corresponding change in a single amino acid (for reviews, see Monaghan et al., 1989, Seeburg, 1993, Hollman and Heinemann, 1994). In addition, glutamate activates a family of G-protein coupled receptors, referred to as metabotropic glutamate receptors (for reviews, see Conn and Patel, 1994, Nakanishi, 1994). Both families of receptors are situated on various aspects of an excitatory synapse, including the pre-synaptic terminal, the post-synaptic terminal, and astrocytes that sheath the synapse (Fig. 1) (for reviews, see Schoepp and Conn, 1993, Engelman and MacDermott, 2004). In addition, these receptors are found on other cells in the CNS. The various localizations of some of these receptors are consistent with the notion that some of these receptors function as sensors to an accumulation of glutamate. For example, activation of some of the presynaptic receptors dampens release of glutamate. In addition, there is now pretty clear evidence that excitatory cell-to-cell signaling is not restricted to that observed between neurons; astrocytes release glutamate and express glutamate receptors (for reviews, see Carmignoto, 2000, Haydon and Carmignoto, 2006). Oligodendroglia also expresses glutamate receptors (for review, see Butt, 2006).

Compared to essentially all other neurotransmitters, the levels of glutamate are extremely high in the mammalian CNS approaching 5–10 mmol/kg (Butcher and Hamberger, 1987); these levels are ∼1000-fold higher than those of many other important neurotransmitters, such as dopamine, norepinephrine, and serotonin. The levels of aspartate are nearly as high as those for glutamate (1–5 mmol/kg). The notion that aspartate may be a neurotransmitter (for review, see Robinson and Coyle, 1987) has fallen out of favor because it is not a substrate for the cloned vesicular transporters that package glutamate into vesicles (Bellocchio et al., 2000, Takamori et al., 2000) nor is it a substrate for the vesicular uptake measured in brain tissue (Naito and Ueda, 1985). However, aspartate is excitatory and does activate at least some of the glutamate receptors (for review, see McDonald and Johnston, 1990). The extracellular concentrations of glutamate, aspartate, and other endogenous excitatory amino acids need to be kept low to limit tonic activation of receptors and to ensure that the depolarization-evoked release of glutamate is accompanied by a sufficient increase in glutamate receptor activation and subsequent signaling. In addition, it has long been recognized that excessive activation of glutamate receptors can kill the cells that express these receptors (for reviews, see Meldrum and Garthwaite, 1990, Choi, 1992). Many of the receptors are activated by low micromolar (1–10 μM) concentrations of these amino acids, and somewhat higher concentrations of these amino acids (10–100 μM) easily kills neurons maintained in culture (Choi et al., 1987).

There is no evidence for extracellular metabolism of glutamate or aspartate (for review, see Schousboe, 1981). This implies that these amino acids need to be cleared from the extracellular space by transporters, and it is generally thought that these amino acids are cleared by a family of Na+-dependent ‘high-affinity’ transporters (for reviews, see Gegelashvili and Schousboe, 1997, Seal and Amara, 1999, Danbolt, 2001, Shigeri et al., 2004). The rationale is based on several observations. First, Na+-independent transport does not contribute more than a few percent of total accumulation of radiolabeled substrate in brain membrane fractions or in cultures prepared from brain tissue (Weiler et al., 1979; for review, see Robinson, 1998). Second, the capacity for Na+-dependent transport can be quite high in both brain membrane preparations and in primary cultures with Vmax values of up to 15 nmol/mg protein per min (Garlin et al., 1995). Third, the densities of the Na+-dependent transporters are remarkably high (Chaudhry et al., 1995, Lehre et al., 1995). Finally, as will be described throughout this review, manipulations (pharmacologic or genetic) that decrease transporter activity have profound effects in the nervous system.

Although there is some variation in the Km values reported for both glutamate and aspartate, they are generally in the low μM range (1–10 μM) for the high-affinity process (for review, see Robinson and Dowd, 1997). This implies that these transporters will be most effective at responding to changes in glutamate concentrations in this range. These transporters function as symporters co-transporting 2 or 3 molecules of Na+ and a proton with each molecule of glutamate (or aspartate). To complete the cycle, a K+ ion is counter-transported resulting in reorientation of the transporter such that the glutamate binding site is once again accessible to the extracellular environment (Zerangue and Kavanaugh, 1996, Levy et al., 1998). There is also evidence that there are low-affinity uptake systems with Km values in the low mM range (Logan and Snyder, 1972), but this system may be Na+-independent (Bennett et al., 1973) and a specific gene product that mediates this activity may not have been identified (for discussion, see Danbolt, 2001). In addition, there is a transport system that mediates the exchange of glutamate for cystine (Bannai, 1986, Ishii et al., 1992). Under physiologic conditions, this transporter provides a source of cysteine to cells that need to produce glutathione. This process, termed system Xc, seems to be a relatively low capacity system, but inhibitors of this transport system substantially decrease extracellular glutamate in microdialysis studies (Baker et al., 2002). It was proposed that this process controls extrasynaptic glutamate. This system does not transport aspartate, so this system would not prevent a toxic accumulation of this potential excitotoxin (for discussion, see Gochenauer and Robinson, 2001).

Five different Na+-dependent high-affinity glutamate transporters have been identified; these transporters share approximately 50–60% amino acid sequence similarity. Based on the recent elucidation of the crystal structure of a bacterial glutamate transporter homologue (Yernool et al., 2004), the transporters are predicted to have 8 transmembrane domains with intracellular carboxyl and amino termini and most likely exist as trimers (Yernool et al., 2003, Koch and Larsson, 2005). Two of these transporters are called GLAST (Storck et al., 1992) and GLT-1 (Pines et al., 1992); these are also called EAAT1 or EAAT2, respectively (Arriza et al., 1994). There are several variants of GLT-1 that originate from alternate splicing of mRNA and these variants differ in their carboxyl- and amino-terminal sequences (Reye et al., 2002a, Reye et al., 2002b, Rauen et al., 2004, Sullivan et al., 2004). Both GLT-1 and GLAST are found primarily on astrocytes (Rothstein et al., 1994, Lehre et al., 1995). Two lines of evidence suggest that these two glial transporters are not uniformly distributed on the astrocytic membrane. First, GLT-1 protein co-localizes with the synaptic vesicle protein synaptophysin (Minelli et al., 2001). Second, quantitative electron microscopic analysis shows that GLT-1 and GLAST are enriched on astrocytic processes near synaptic termini, suggesting that they are targeted to portions of the membrane that are near the synapse (Chaudhry et al., 1995, Lehre et al., 1995). These transporters are also found on many other cells, such as oligodendroglia and macrophages (Domercq et al., 1999, Gras et al., 2003). There is also evidence that GLT-1 can be expressed by neurons during development, in the adult nervous system, and in primary cultures (Schmitt et al., 1996, Furuta et al., 1997a, Brooks-Kayal et al., 1998, Mennerick et al., 1998, Sullivan et al., 2004, Berger et al., 2005); at least some of this protein is found on presynaptic nerve terminals (Schmitt et al., 2002, Chen et al., 2004). Two members of the transporter family, EAAC1 (also called EAAT3) and EAAT4, are generally considered neuronal transporters (Rothstein et al., 1994, Furuta et al., 1997b), but on many neurons they appear to localize to post-synaptic elements, suggesting that they do not participate in transmitter recycling in a fashion analogous to that observed for monoamine transporters (for review, see Blakely and Bauman, 2000, Torres et al., 2003). EAAC1 is unevenly distributed on the post-synaptic spine with lower levels in the post-synaptic density (enriched in some glutamate receptors) and with higher levels in perisynaptic regions (He et al., 2000, He et al., 2001). Although expression of EAAC1 is enriched in pyramidal neurons of the hippocampus and cortex, it is also expressed by many other glutamatergic neurons, by GABA-ergic neurons (Rothstein et al., 1994), and by oligodendroglia (Conti et al., 1998). There is some evidence that low levels of EAAC1 are observed in astrocytes (Conti et al., 1998, Schlag et al., 1998). EAAT4 expression is generally thought to be restricted to GABA-ergic Purkinje cell neurons of the cerebellum in opposition to terminals that release glutamate (Fairman et al., 1995, Furuta et al., 1997b), but can also be found in astrocytes (Hu et al., 2003). Finally, EAAT5 expression seems to be restricted to rod photoreceptor and bipolar cells of the retina (Arriza et al., 1997).

In considering the role of transporters in controlling excitatory synaptic transmission, it is important to remember that the time required for a transporter to complete the translocation of glutamate across the membrane is between 10 and 75 ms (Wadiche et al., 1995b, Bergles and Jahr, 1997). This is much slower than the time course for many of the fast excitatory responses recorded throughout the nervous system; these can be as fast as 10 ms. Therefore, other mechanisms probably contribute to the rapid time-course, including desensitization of some types of glutamate receptors (Tang et al., 1989). However, the density of transporters situated near the synapse is sufficient to diminish the amount of released glutamate that is available for activation of glutamate receptors; they appear to essentially act as buffers with binding to the transporters being sufficient to limit receptor activation (Tong and Jahr, 1994, Diamond and Jahr, 1997; for reviews, see Conti and Weinberg, 1999, Huang and Bergles, 2004).

Under physiological conditions, it appears that neuronal and glial glutamate uptake effectively limits glutamate spillover, so that most synapses function independently, and only a small amount of glutamate is able to diffuse away to activate neighboring synapses (reviewed in Vizi, 2000, Vizi and Mike, 2006). However, extrasynaptic signaling appears important under different conditions, for instance in area CA1 of the hippocampus there is intersynaptic spillover during synchronous activity. In addition, there is evidence that NMDA receptors located both intra- and extrasynaptically can be activated by glutamate released from more than one synapse during long-term potentiation. Glutamate can also activate presynaptic receptors to modulate transmitter release. Furthermore, there is some tonic activation of extrasynaptic glutamate receptors by ambient transmitter levels.

Based on several lines of evidence, it appears the GLT-1/EAAT2 has the predominant role in clearing glutamate throughout the neuroaxis (for review, see Robinson, 1999, Danbolt, 2001). In fact, there is reasonable evidence that GLT-1 may represent up to 1% of brain protein (for review, see Danbolt, 2001). It has been somewhat easier to define roles for GLT-1 because relatively selective pharmacological inhibitors have been identified, such as dihydrokainate and WAY-855 (Arriza et al., 1994; for reviews, see Robinson and Dowd, 1997, Bridges and Esslinger, 2005, Dunlop, 2006). Although it has been more difficult to define a precise role for GLAST, the density of this transporter approaches that of GLT-1 (Lehre et al., 1995) and is enriched even further in some specialized locations such as Bergmann glia, glia in the vestibular end organ, and Muller cells of the retina (for review, see Huang and Bergles, 2004). Understanding the role of the neuronal transporters has also been somewhat difficult. There is evidence that EAAC1 transports glutamate into GABA-ergic nerve terminals, providing glutamate as a precursor for GABA synthesis (Sepkuty et al., 2002, Mathews and Diamond, 2003). A post-synaptic neuronal transporter has been implicated in controlling the spillover of glutamate between synapses in hippocampus (Rothstein et al., 1994, Diamond, 2001). Since EAAC1 is essentially the only transporter found in this location (Rothstein et al., 1994), it suggests that the intermixing of EAAC1 and post-synaptic receptors may locally regulate receptor activation. At least a few of these transporters can also transport cysteine (the reduced form of cystine), suggesting that they might also subserve a role in providing this important precursor for the synthesis of the endogenous anti-oxidant, glutathione (for review, see McBean, 2002). In this regard, mice deleted of EAAC1 display a neurodegenerative process that is associated with decreased brain glutathione levels and is reversed by providing an alternate source of intracellular cysteine, N-acetylcysteine (Aoyama et al., 2006). In addition to stoichiometrically transporting substrate, the binding of substrate to these transporters results in activation of a Cl channel that is apparently intrinsic to the transporters themselves. The largest currents observed are associated with neuronal transporters (Fairman et al., 1995, Wadiche et al., 1995a, Arriza et al., 1997; for reviews, see Slotboom et al., 2001). In fact, EAAT4 appears to be relatively inefficient at translocating substrate with a very slow turnover number, suggesting that the more prominent role of EAAT4 may be to serve as a ligand-gated anion channel (Mim et al., 2005). Similarly, a recent study provides compelling evidence that EAAT5 on the rod bipolar cells of the retina may control transmitter release by hyperpolarizing the presynaptic nerve terminal (Veruki et al., 2006), but it also has a role in controlling extracellular glutamate in the retina (Hasegawa et al., 2006).

Like many proteins, these transporters are regulated by both transcriptional and post-transcriptional mechanisms. These regulatory mechanisms have been the topic of many recent reviews (Gegelashvili and Schousboe, 1997, Danbolt, 2001, González and Robinson, 2004, Beart and O'Shea, 2007, Robinson, 2006); therefore we will only highlight the examples of some of the mechanisms that may be relevant to understanding the alterations in glutamate transporters that have been observed under pathological conditions. Approximately a decade ago, several groups realized that GLT-1 is essentially not expressed by astrocytes in culture even though it is easily detected in brain tissue. Co-culturing neurons with astrocytes induces expression of GLT-1 in astrocytes (Gegelashvili et al., 1997, Swanson et al., 1997, Schlag et al., 1998). At least part of this effect can be mimicked using conditioned media from neuronal cultures (Gegelashvili et al., 1997) or by maintaining neurons on a semipermeable membrane over a monolayer of astrocytes (Schlag et al., 1998). This suggests that secreted factors contribute to induction of GLT-1. Based on the observation that the level of induction of GLT-1 expression caused by conditioned media or in the transwells is quite small, it seems likely that both contact and secreted factors contribute to the regulation of GLT-1. Although a number of exogenously applied factors mimic the effects of neurons, it is still not clear which of these factors are sufficient to induce GLT-1 expression to the levels observed in vivo (Eng et al., 1997, Swanson et al., 1997, Schlag et al., 1998, Figiel and Engele, 2000, Zelenaia et al., 2000, Aronica et al., 2003, Rodriguez-Kern et al., 2003, Zschocke et al., 2005), but some of these factors activate the GLT-1 promoter (Su et al., 2003, Sitcheran et al., 2005). Excitotoxic destruction of neurons in mixed cultures of neurons and astrocytes results in decreased expression of GLT-1 and a robust increase in GLAST expression in the remaining astrocytes within 7 days (Schlag et al., 1998). Similarly, lesioning of projection neurons or deafferentation reduces expression of GLT-1 in target areas in vivo; decreases in GLAST expression were also observed (Ginsberg et al., 1995, Ginsberg et al., 1996, Levy et al., 1995). Based on this data, it seems highly likely that neurons contribute to induction and to the maintenance of GLT-1 expression both in vitro and in vivo. These observations have potential implications for understanding the mechanisms that might contribute to decreased expression of GLT-1 and/or GLAST that accompanies many different neurodegenerative disorders (see below). It also seems that some of the decreases in GLT-1 expression described below may simply be an epiphenomenon of neurodegeneration rather than causative.

In addition to transcriptional mechanisms, there is evidence that the activity of many of the glutamate transporters can be acutely (within min) regulated by mechanisms that are independent of changes in the expression of the transporters (for review, see Robinson, 2002, Beart and O'Shea, 2007). Some of these effects are associated with a redistribution of the various transporters to or from the plasma membrane in response to activation of a variety of signaling molecules (Davis et al., 1998, Duan et al., 1999, Sims et al., 2000, Kalandadze et al., 2002, Levenson et al., 2002, Najimi et al., 2002, Najimi et al., 2005, Zhou and Sutherland, 2004, Guillet et al., 2005, O'Shea et al., 2006). In addition, there is reasonable evidence that the catalytic efficiency or turnover number of the transporters might be regulated, but at present it is not clear how this might be accomplished (for a recent discussion, see Robinson, 2006). While these acute effects represent mechanisms that may be altered under pathologic conditions, most analyses have understandably focused on measuring protein and/or mRNA levels in human autopsy tissue from individuals with neurodegenerative diseases and in animal models of these diseases. Therefore, we are even further from linking this type of regulation to neurodegenerative diseases than we are from linking possible transcriptional events.

For over 40 years, it has been recognized that glutamate and glutamate receptor agonists can cause toxicity in the nervous system (for reviews, see Olney, 1989, Choi, 1992, Coyle and Puttfarcken, 1993, Greene and Greenamyre, 1996, Doble, 1999). Although acidic amino acids are not thought to readily cross the blood brain barrier, they do seem to enter the brain when the blood brain barrier is either not fully formed, such as is observed early in development, or when the blood brain barrier is compromised by injury as would occur with trauma or swelling. In fact, one of the first studies to demonstrate evidence for glutamate-mediated toxicity was performed in young mice with peripheral injections of glutamate (Olney, 1969). During the subsequent 20 years, it became clear that several different non-endogenous excitatory amino acids cause neurotoxicity and the patterns of damage including regional and cellular specificity resembled that observed in neurodegenerative diseases, such as Huntington's disease (Beal et al., 1986, Storey et al., 1992). In addition, several studies demonstrated that acute insults such as stroke or traumatic injury are associated with increases in the extracellular concentrations of glutamate and aspartate (Butcher et al., 1987, Faden et al., 1989). Finally, in the late 1980s, it was demonstrated that glutamate receptor antagonists can attenuate the damage observed in animal models of these same acute insults (for review, see Chen and Lipton, 2006). These observations prompted several years of drug discovery efforts directed toward the development of glutamate receptor antagonists. Based on these efforts, there is very strong evidence that excessive activation of glutamate receptors can cause cell death both in vitro and in vivo. It is not completely clear why these efforts were not successful, although some of these agents have neurotoxic effects (for review, see Ikonomidou and Turski, 2002). In addition, some have psychotomimetic effects by blocking the NMDA subtype of glutamate receptor.

In addition to causing cell death through excessive activation of glutamate receptors, an extracellular accumulation of glutamate can also cause toxicity through an interaction with system Xc (Murphy et al., 1990). As indicated above, this transporter is thought to normally stoichiometrically exchange extracellular cystine for intracellular glutamate, so as to provide a source of cysteine for the synthesis of glutathione. Lewerenz et al. (2006) demonstrated that glutamate neurotoxicity in the HT22 neuronal cell line results from excess extracellular glutamate blocking system Xc. Over-expression of an Xc subunit and EAAT3 cooperatively protects against glutamate toxicity by decreasing the amount of extracellular glutamate available to block Xc, thereby preventing glutathione depletion. This type of damage is clearly attenuated by anti-oxidants.

Many of the original inhibitors of these transporters are substrates and are often referred to as ‘substrate-inhibitors’ (Arriza et al., 1994; for review, see Campiani et al., 2003, Bridges and Esslinger, 2005). As the name implies, these compounds are translocated by the transporters, much like glutamate or aspartate. There are several problems with using these types of compounds in vivo and even in culture. Particularly in vivo the capacity for clearance is apparently so high that the compounds cannot diffuse very far from where they are injected (for discussion, see Garthwaite, 1985). This means that the concentrations of inhibitor need to be higher than is required to acutely block glutamate transporters because of the continuous clearance; this could at least theoretically result in non-specific effects through interactions with other extracellular targets (e.g. receptors). In addition, these compounds will likely accumulate in the cells that express high levels of transporters, potentially leading to additional non-specific effects through interactions with intracellular targets. In fact, original in vivo studies failed to demonstrate a role for glutamate transporters in excitotoxicity, but these studies were dependent upon using these substrate inhibitors (Mangano and Schwarcz, 1983, Massieu et al., 1995). In a cell culture model, one of the more selective substrate-inhibitors potentiates glutamate toxicity (Robinson et al., 1993) and increases the sensitivity of neurons to oxygen–glucose deprivation (Dugan et al., 1995). Similarly, the substrate inhibitor trans-pyrrolidine-2,4-dicarboxylate (t-PDC) causes both NMDA-dependent neurotoxicity and NMDA-independent gliotoxicity in hippocampal mixed cultures (Guiramand et al., 2005). The mechanism of trans-pyrrolidine-2,4-dicarboxylate induced gliotoxicity remains unclear, but it is also independent of oxidative stress and glutathione deficiency. As mentioned above, transportable inhibitors have the potential to affect intracellular targets, which is one possible explanation to account for gliotoxicity. On the other hand, blockade of glutamate transporters by the non-transportable glutamate uptake inhibitor threo-β-benzyloxyaspartate (TBOA) is neurotoxic through activation of NMDA receptors but is not toxic to glia (Guiramand et al., 2005). Glutamate transporters also play an important role in protecting against necrotic death. In a series of experiments, Bonde and colleagues have shown that blocking glutamate transporters with threo-β-benzyloxyaspartate under normal conditions in rat hippocampal slice cultures results in marked necrotic neurodegeneration, presumably due to increased glutamate in the synaptic cleft, as the effect is blocked by glutamate receptor antagonists (Bonde et al., 2005). In addition, threo-β-benzyloxyaspartate exacerbates ischemia in rat hippocampus (Selkirk et al., 2005b). In culture, uptake into glia has a dramatic effect on the sensitivity of neurons to excitotoxic insults (Rosenberg et al., 1992, Dugan et al., 1995). With the cloning of the transporters, several additional tools became available to manipulate glutamate transporter activity. Using anti-sense knockdown, Rothstein and his colleagues demonstrated that impaired glutamate transporter expression was associated with neurodegeneration in normal animals (Rothstein et al., 1996). In addition, mice deleted of GLT-1 display markedly diminished transport activity, seizures, and increased sensitivity to neurotoxicity (Tanaka et al., 1997), convincingly demonstrating that impaired glutamate transport can cause neurodegeneration in an otherwise normal setting. However, the extent to which glutamate transport needs to be impaired to cause CNS damage is not clear. Although this is only based on intuition, it seems somewhat unlikely that a 10% (or maybe even 20%) decrease in transporter expression would necessarily lead to neurodegeneration, unless larger localized changes accounted for the rather modest reduction in total expression. With that in mind, alterations in glutamate transporters have been reported for several neurodegenerative disorders including amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. It is not clear in most cases whether glutamate dysfunction contributes to pathogenesis, or results from the disease pathology. It is important to determine whether the onset of neurodegeneration precedes or follows glutamate transporter alterations. In any case, decreases in transporter expression could contribute to ongoing pathology by making the tissue more vulnerable to excitotoxicity.

Section snippets

Glutamate transporters in amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease observed in adults with a prevalence of 2–3 per 100,000 individuals. It is characterized by a progressive loss of motor neurons and is generally fatal within 1–5 years of onset (for review, see Cleveland and Rothstein, 2001). The degeneration is more pronounced in the motor neurons of the spinal cord and brainstem, but degeneration is also observed in the motor cortex. The majority

Reversal of glutamate transporters

A common theme emerging from many of the neurological disorders discussed is that decreased expression and function of glutamate transporters may contribute to excitotoxicity associated with many of these disorders. Therefore, would treatment targeted towards upregulating glutamate transporters offer neuroprotection? And are there any possible deleterious side effects of over-expression of glutamate transporters? As previously mentioned, glutamate transporters reverse when the Na+/K+

Conclusion

Alterations in glutamate transporter expression and/or function have been implicated increasingly in a variety of neurological disorders. It is important to attempt to determine whether these changes contribute to pathogenesis or result from existing pathology. In many cases, the role of glutamate transporters in pathogenesis is still unclear, due to conflicting results, possibly due to differing methodology. Although their reversal can actually lead to elevated extracellular concentrations of

Acknowledgments

The authors are supported by grants from the National Institutes of Health (A.L.S. NS39011 and MH071008; M.B.R. NS39011, NS36465, and NS29868).

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