To obtain higher resolution, thinner sections were needed. By using dry mount autoradiography Young and Kuhar ; Danbolt et al. However, heteroexchange complicated the interpretations as the amount of retained radioactively labeled ligand was dependent on both the number of transporter molecules and by the amount of endogenous dicarboxylic amino acid trapped within the membranes Danbolt and Storm-Mathisen a , b ; Danbolt From the early days of glutamate research, it was believed that glutamate is taken up by glutamatergic nerve terminals Fonnum , but the finding that glial glutamate transporters are down-regulated after glutamatergic denervation Levy et al.
By incubating tissue slices in d -aspartate and fixing the slices, it was possible to detect fixed d -aspartate with antibodies. With this technique, uptake in both astrocytes and nerve terminals was demonstrated at the electron microscopic level Gundersen et al. After the protein sequences of the transporters were known, synthetic peptides could be used to generate antibodies to the transporters themselves Danbolt et al.
This led to an explosion in the use of antibodies to transporters, but, unfortunately, not all investigators validated their antibodies and procedures well enough for detailed discussion see Holmseth et al. The most difficult part is to obtain good negative controls. Antibodies may react with seemingly unrelated proteins Holmseth et al.
In fact, antibody binding can always be achieved see for instance Fig. This is just a question of adjusting the assay conditions.
Without a good negative control e. Therefore, antibody binding does not in itself prove that a given antigen is present. In this context it should be noted that the so called pre-adsorption test can easily give a false impression of specificity Holmseth et al. Whenever possible, it is a good idea to use additional methods, including in situ hybridization and Western blotting in combination with immunocytochemistry. Lehre et al. Another approach is to search available transcriptome and proteome datasets.
Together, these data cast doubt over a large number of immunocytochemistry reports. The reason is obvious. Labeling with antibodies can always be obtained, and without good negative controls, it is not possible to tell if the labeling represents the antigen of interest or artifacts see Holmseth et al.
Also note that water soluble proteins present in the samples may inhibit binding of transporters to the blotting membranes Zhou et al. Thus, strong upregulation of other proteins should be considered a potential source of error when estimating transporter levels by immunoblotting.
Electron microscopy in combination with pre-embedding immunocytochemistry without detergents on unfrozen tissue is ideal for identification of labeled cell types, but is not ideal for subcellular distribution as the peroxidase reaction product diffuses some distance before precipitating. Depending on the strength of the reaction, the reaction product may diffuse a couple of hundred nanometers. In contrast, post-embedding immunogold is better for collecting semi-quantitative data and gives better intracellular resolution, but when cell membranes are labeled and cells are close to each other as they typically are in the brain, then immunogold cannot tell which membrane labeling belongs to for description of these methods, see Danbolt et al.
Another problem with post-embedding immunogold is that there must be a sufficient number of target molecules in the plane of the section. These proteins are present at very high concentrations Dehnes et al.
This explains, in part, why our early localization studies were so successful Chaudhry et al. In contrast, EAAT3 is expressed at lower levels resulting in too few molecules per micrometer plasma membrane length to distinguish real labeling from background noise Holmseth et al.
The antibodies do not penetrate well into the sections. To maximize labeling, the section may be mounted so that they can be labeled on both sides. Thus, the sensitivity of the post-embedding immunogold technique is limited by the number of proteins in the exact section plane.
Another challenge follows from the vulnerability of the sections and thereby also the labeling. These sections are easily damaged during processing. Consequently, there is variability and this leads to another challenge: avoiding sampling error.
This challenge comes in addition to those mentioned above specificity, proteolysis, etc. It is also important to consider if any detected proteins are expressed at physiologically relevant levels. The number of molecules needed to accomplish a given task depends on what that task is. This consideration is particularly relevant for neurotransmitter transporters because the transport process is fairly slow.
This means that the number of transporters must be high. There is a rapid extracellular turnover of glutamate Jabaudon et al. Because the km-values are about 1, times higher Danbolt , maintenance of such low extracellular levels implies a vast excess of transporter proteins Bergles and Jahr ; Dehnes et al.
A large number of papers on transporter distributions have been published, and it is not easy to navigate in the literature as many of the statements are corrected in later publications.
A schematic illustration of glutamate transporter distributions around synapses close to a blood vessel in the hippocampus. Four glutamatergic nerve terminals T are shown forming synapses onto dendritic spines S. Astrocyte branches are indicated G.
Note that astrocytes have very high densities Lehre et al. Also note that glutamate transporters have not been detected in the endothelium. EAAT1 is selective for astrocytes Lehre et al. EAAT3 green dots is selective for neurons, but is expressed at levels two orders of magnitude lower than EAAT2 and is targeted to dendrites and cell bodies Holmseth et al.
Also note that the endfeet may actually overlap with no gaps in between them Mathiisen et al. This conclusion is supported both by in situ hybridization and immunocytochemistry e. Ginsberg et al. Thus, there is no disagreement here. Other statements can be found in the literature, but these have been corrected by the authors themselves. This revealed that EAAT1 is preferentially targeted to the plasma membranes, and that plasma membranes facing neuropil have higher densities than those facing cell bodies, pia mater and endothelium Fig.
The EAAT1 knockout mice also display poor nesting behavior; abnormal sociability, reduced alcohol intake and reward Watase et al. In the mature and normal brain it is predominantly expressed in astrocytes Danbolt et al. There is no disagreement here either, and this conclusion is supported both by later immunocytochemistry e. Schmitt et al. The discussion about EAAT2 distribution concerns expression in neurons.
Having said that, there is consensus that EAAT2 is expressed in cultured neurons from hippocampus and neocortex; in particular if these are cultured in the absence of astrocytes Mennerick et al.
There is also consensus that EAAT2 is present in neurons in the normal and mature mammalian retina Rauen et al. The controversy is related to expression of EAAT2 in neurons in the normal and mature brain cerebrum and cerebellum. The remaining controversy concerns a the expression of EAAT2 in axon-terminals in other parts of the brain, and b the physiological importance of the uptake into terminals.
This disproportionally large uptake cannot simply be disregarded as an in vitro artifact due to a higher rate of heteroexchange than net uptake Zhou et al. Preliminary data from selective deletion of EAAT2 in axon-terminals indicate disturbances in synaptic transmission Sun et al. However, further studies are required before definite conclusions can be made. This explains why EAAT2-knockout mice are inconspicuous at birth. They have increased extracellular glutamate levels Mitani and Tanaka ; Takasaki et al.
Nevertheless, the first studies were basically correct Kanai and Hediger ; Rothstein et al. EAAT3 is a neuronal transporter, and is not expressed in glial cells Holmseth et al.
It appears to be expressed in the majority if not all neurons throughout the CNS, but has a unique sorting motif Cheng et al. The highest levels of EAAT3 in the brain are found in the hippocampus and neocortex, but the total tissue content in young adult rat brains is about times lower than that of EAAT2 Holmseth et al. It is also expressed in the kidney and in the ileum. EAAT4 knockout mice are viable and appear normal Huang et al. EAAT5 slc1a7 is preferentially expressed in the retina, while the levels in the brain are low Arriza et al.
EAAT5 is also expressed in vestibular hair cells and calyx endings Dalet et al. There is more than one isoform in the retina due to variable splicing Eliasof et al. As explained above, EAAT4 and EAAT5 are not very efficient as transporters, but are efficient chloride channels suggesting that they may be more important as inhibitory glutamate receptors than as transporters. Some investigators have tried to determine the exact cellular and subcellular localization of EAAT5, but the validity of these studies is hard to judge at present because nobody has as yet made an EAAT5 knockout mouse that could serve as negative control for validation of the immunolabeling.
We have previously shown how important this control is and also how inadequate the so called pre-adsorption test is Holmseth et al.
So, validated information on EAAT5 distribution remains to be provided. Glutamate taken up by astroglial cells can be metabolized via the tricarboxylic acid cycle and be used in protein synthesis or converted to glutamine. Glutamine can be released to the extracellular fluid by a sodium neutral amino transporter in the astrocytic membrane by SNAT3 Boulland et al.
Glutamine synthetase plays important roles in the brain and in other organs from implantation to high age. This is evident from studies of glutamine deficiency in man and mice He et al.
Further, reduced glutamine synthetase levels are associated with some forms of epilepsy Eid et al. The prevailing view has been that glutamine from astrocytes is the predominant source of glutamate in glutamatergic terminals Sibson et al.
And although there are many observations in cultured cells suggesting the existence of glutamine transporters in glutamatergic terminals, it is important to keep in mind that cultured astrocytes are different from mature astrocytes e. Plachez et al. Further, it is important to note that glutamine transporters have so far not been positively identified in terminals in brain tissue Mackenzie and Erickson ; Chaudhry et al.
Jenstad et al. One possibility is that they have evaded detection in glutamatergic terminals due to methodological challenges. Another possibility is that they have not been detected simply because they are not there. There could be other glutamine transporters, however.
There are also other potential candidates within the slcfamily. On the other hand, lack of significant glutamine uptake activities in terminals would be is in line with some old reports e. Hertz et al. A third source is direct uptake by glutamate transporters in terminals themselves Gundersen et al. Another complicating factor is that nerve terminals in different brain regions may differ. While terminals in several forebrain regions e.
Gundersen et al. Wilkin et al. In conclusion, the glutamine-glutamate cycle has been studied and debated for about 50 years and we still do not have the final answer! The nervous system isolates itself from blood by means of barriers e. Abbott ; Alvarez et al. This is important for a number of reasons. The blood—brain barrier is between blood and the interstitial fluid of the brain.
It is in mammals formed by the endothelial cells after influence from brain cells. Another barrier is in the choroid plexus epithelium which secretes cerebrospinal fluid CSF. These barriers are important both from a physiological point of view because they are essential for brain homeostasis, and from a pharmacological point of view because they prevent drugs from entering brain tissue Deboer and Gaillard ; Teichberg The literature is extensive and full of conflicting reports.
Here we only want to point out Fig. There are, however, huge amounts of glutamate transporters in the astrocytic endfeet surrounding the blood vessels Fig.
When isolating brain microvessels, the preparations are likely to be contaminated by endfeet and this may explain some of the data. Thus, it seems that no significant transport of glutamate can occur through a normal and intact blood—brain barrier. In agreement, injection of radiolabeled glutamate and aspartate does not result in accumulation of radioactivity in the brain Klin et al. On the other hand, there is an efflux mechanism for glutamate as blood-mediated scavenging is reported to reduce glutamate in the cerebrospinal fluid Gottlieb et al.
There is some evidence that this may offer some protection Zlotnik et al. The mechanism, however, of release from the brain remains to be identified. This illustrates that brain water homeostasis and transport mechanisms between the blood and the extracellular fluid in brain are incompletely understood. Recent work from Nedergaard and co-workers may represent a leap in our understanding. This may reconcile a number of apparently conflicting reports. As outlined above, substantial progress has been made over the last decades.
But there are major gaps in our understanding of key processes. One example is transport of metabolites across the blood brain barrier. Another unknown is the uptake in glutamatergic nerve endings and the relevance of the glutamate-glutamine cycle for transmitter glutamate. A third topic is why the body needs several different glutamate transporters, and how they can be pharmacologically modulated.
The authors thank Gunnar Lothe for help with Fig. National Center for Biotechnology Information , U. Journal of Neural Transmission.
J Neural Transm Vienna. Published online Mar 1. Zhou and N. Box , Oslo, Norway Find articles by Y. Box , Oslo, Norway Find articles by N.
Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Nov 1; Accepted Feb Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author s and the source are credited. This article has been cited by other articles in PMC. Abstract Glutamate is the most abundant free amino acid in the brain and is at the crossroad between multiple metabolic pathways.
Table 1 Overview of the nomenclature of plasma membrane glutamate transporters. Open in a separate window. The glutamate-cystine exchanger Another transporter that has got quite a lot of attention lately is the so called glutamine-cystine exchanger xCT; slc7a Intracellular glutamate carriers When glutamate enters the cytoplasm, it may undergo further redistribution to mitochondria or synaptic vesicles Erecinska and Silver ; Nicholls Release of glutamate Glutamate is continuously being released to the extracellular fluid, and inhibition of glutamate uptake leads to extracellular buildups of glutamate within seconds Jabaudon et al.
Regulation of the EAAT-type of transporters Considering the importance of the glutamate transporters, pharmacological manipulation of transporter function may prove to be highly interesting from a therapeutic point of view Sheldon and Robinson Approaches used to localize glutamate transporters Early attempt to localize glutamate uptake sites were done using autoradiography in combination with tissue slices or synaptosome preparations e. Cellular and subcellular distribution of glutamate transporters in normal mature brain tissue A large number of papers on transporter distributions have been published, and it is not easy to navigate in the literature as many of the statements are corrected in later publications.
Comments on the glutamine-glutamate cycle Glutamate taken up by astroglial cells can be metabolized via the tricarboxylic acid cycle and be used in protein synthesis or converted to glutamine. Glutamate transporters at the blood brain barrier The nervous system isolates itself from blood by means of barriers e. Concluding remarks As outlined above, substantial progress has been made over the last decades.
Acknowledgments The authors thank Gunnar Lothe for help with Fig. References Abbott NJ. Dynamics of CNS barriers: evolution, differentiation, and modulation. Cell Mol Neurobiol. J Neurochem. Glial influence on the blood brain barrier.
Immunogold cytochemistry in neuroscience. Nat Neurosci. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Cloning and expression of a human neutral amino acid transporter with structural similarity to the glutamate transporter gene family. Abnormalities in glutamate function can disrupt nerve health and communication, and in extreme cases may lead to nerve cell death. Nerve cell dysfunction and death leads to devastating diseases, including ataxia, ALS, GAD and other neurological and neuropsychiatric disorders.
Figure 4. Potential mechanisms that lead to excitotoxicity in AD. Altered calcium homeostasis and increased sensitization of NMDA receptors in AD renders neurons more sensitive to excitotoxicity. This is further amplified by the upregulation of extracellular glutamate via downregulation of EAAT2 and upregulation of system x c -.
HD is a dominantly inherited, fatal neurodegenerative disease caused by a trinucleotide CAG repeat expansion in the coding region of the huntingtin htt gene that leads to the degeneration of GABAergic medium-sized spiny neurons MSN in the striatum, although other brain regions are also affected as the disease progresses.
HD presents as a movement disorder with co-morbid psychiatric and cognitive symptomatology Nance, Early findings that suggested that excitotoxicity might play an important role in HD were based on the observation that injection of the KYN metabolite and NMDA receptor agonist QUIN, as well as L-glu and kainate, into the striatum of rats generated neuronal degeneration Coyle and Schwarcz, ; Beal et al.
Beal et al. Later, NMDA receptors were found to be hyperactive and striatal neurons from different HD mouse models, including those transgenic for a yeast artificial chromosome YAC that leads to over-expression of full-length htt with extended polyglutamine repeats Zeron et al.
Of note, in vivo , a sensitization to excitotoxin injection into the striatum was only observed in the transgenic YAC model of HD Zeron et al. However, this acquired neuroprotection is not specific for NMDA receptor agonists but extends to other neurotoxic insults Hansson et al.
More recently, data have been presented that suggest that not only the subunit composition but also the localization of NMDA receptors might play an important role in the deleterious NMDA receptor activity in HD. Milnerwood et al. As expected from in vitro studies Hardingham et al. One pathway that might mediate the sensitization to excitotoxic stimuli downstream of the activation of extrasynaptic NMDA receptors was identified as activation of p38 MAPK Fan et al.
Taken together, multilayered evidence suggests that mutant htt leads to sensitization of MSN to glutamate excitotoxicity in part through a relative redistribution of NMDA receptors, especially those containing an NR2B subunit, from synaptic to extrasynaptic sites. Interestingly, using in situ -hybridization, Arzberger et al. However, extracellular striatal glutamate concentrations were found to be similar to those of wild-type control mice Gianfriddo et al.
Guidetti et al. Taken together, the published literature supports the view that in HD there is a redistribution of NMDA receptors, especially those containing NR2B, which might activate signaling pathways that foster neurodegeneration Figure 5. There is no consistent evidence that extracellular cerebral L-glu levels are grossly increased in HD.
Figure 5. Potential mechanisms that lead to excitotoxicity in HD. Increased redistribution of NMDA receptors to the extrasynaptic compartment is thought to be the prevailing mechanism that fosters excitotoxicity in HD.
Although EAAT2 and the glutamate-lowering kynurenine metabolite kynurenic acid KYNA are downregulated, these changes might be compensated for by a decrease in system x c - expression. As EAATs have been found to be down-regulated in many diseases of the nervous system Sheldon and Robinson, and hypothetically increased L-glu and L-asp clearance should dampen the excitotoxic component of these diseases, many researchers have set out to identify compounds that induce EAAT2, which is the principal EAAT in the brain and most frequently found to be downregulated Sheldon and Robinson, ; Kim et al.
This has led to the identification of many compounds that in vitro Colton et al. Some of these have proven to be protective in animal models of neurodegenerative diseases Rothstein et al. Cef is perhaps the best studied of these compounds and has been tested in models of AD Zumkehr et al.
However, it has to be kept in mind that none of these compounds has been extensively screened for its ability to interact with other cellular pathways that might also be neuroprotective. Since oxidative stress is assumed to play a role in many, if not all, neurodegenerative diseases Bogdanov et al. Indeed, xCT, which is one of the downstream targets of Nrf2, has been found to be upregulated by Cef in vitro and in vivo Lewerenz et al.
Another in vitro EAAT2-inducing compound, MS, effectively protected against secondary neurodegeneration after traumatic brain injury, but through mechanisms other that EAAT2 upregulation Fontana et al. Thus, proof of concept experiments that unequivocally demonstrate the pathophysiological role of a chronically increased excitotoxic input via iGluRs in neurodegenerative diseases require more specific manipulations of the neurotransmitter physiology.
However, this animal model of increased glutamatergic neurotransmission has not yet been used to test whether Glud1 over-expression exacerbates the phenotype of mouse models of neurodegenerative diseases. Another genetically engineered model is the EAAT2-deficient mouse. Heterozygous EAAT2 knock-out mice however develop normally and show only mild behavioral abnormalities Kiryk et al. Consequently, this mouse model of mild glutamatergic hyperfunction has been used in a series of proof of principle studies that investigated the functional role of glutamate in animal models of neurodegenerative diseases.
A modest reduction in survival was also noted in these double mutant mice. Increased EAAT2 protein levels significantly improved cognitive function, restored synaptic integrity, and reduced amyloid plaques in these AD mice Takahashi et al.
However, microglial activation has also been shown to be modulated by system x c - deficiency resulting in a more neuroprotective phenotype Mesci et al. Thus, genetic models support the role of chronic excitotoxicity in neurodegenerative diseases, especially ALS and AD.
Of note, all of these models represent life-long changes in glutamatergic neurotransmission. From the therapeutic perspective, these models cannot predict whether drugs that specifically ameliorate the glutamatergic tone during the neurodegenerative process are protective. To this end, either intensive testing of EAAT2-inducing drugs for their interaction with other signaling pathways or the development of inducible mouse models with dampened excitotoxic load are warranted.
Other pathways including tryptophan metabolism and, especially, the tryptophan metabolite KYNA, modulate glutamatergic neurotransmission. Glutamatergic input on neurons is either via synaptically released L-glu and L-asp acting on synaptic iGluRs or by non-synaptically released L-glu acting at extrasynaptic L-glu receptors.
Chronically increased input via iGluRs, even if it is only moderate, has the propensity to induce neuronal degeneration, so-called chronic excitotoxicity. In many neurodegenerative diseases, including HD, AD, and ALS, multilayered evidence suggests that glutamatergic dysregulation is an important contributor to disease pathology although the molecular basis for this varies widely and might be distinct for each disease and most likely does not represent the only pathway that leads to neurodegeneration.
However, as specific pharmacological tools or inducible genetically engineered mouse models that allow manipulation of glutamatergic input are lacking, it is not known to what extent L-glu dysregulation contributes to disease progression in specific mouse models of different neurodegenerative diseases. Thus, while the idea that chronic excitotoxicity contributes to multiple neurodegenerative diseases is supported by many layers of scientific evidence, it is not clear that therapeutic interventions that re-establish glutamatergic homeostasis during ongoing neurodegeneration will be effective tools for stopping the disease process.
Besides direct modulators of iGluR activity, strong candidates for future approaches to treating chronic excitotoxicity include specific inducers of EAAT2 to stimulate L-glu and L-asp uptake, inhibitors of system x c - to reduce L-glu release as well as compounds that aim to decrease extracellular L-glu by modulating KYN metabolism, e.
In addition, it has to be kept in mind that combinations of these interventions might be required to obtain clinically significant benefits without evoking adverse side effects.
JL provided the concepts for the review and wrote much of it. PM wrote a portion of the review and edited the entire review. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Grant, K. For more on energy metabolism , click here. The defect in energy metabolism results in a decreased amount of energy in the cell , leading to changes in the NMDA receptor.
The NMDA receptor on nerve cells is unique in that it has various properties not found in other types of receptors. While non-NMDA receptors open any time glutamate binds to them, the NMDA receptor needs both the binding of glutamate and an increase in cell charge before it opens.
Because the non-NMDA receptors are not blocked, the binding of glutamate alone opens these receptors and allows positively charged ions to flow into the cell. These ion An atom or group of atoms that carries a positive or negative electric charge as a result of having lost or gained one or more electrons negatively-charged particles.
Because of the activities of these ion An atom or group of atoms that carries a positive or negative electric charge as a result of having lost or gained one or more electrons negatively-charged particles. In HD nerve cells, in contrast, the lower amount of energy available reduces the ability of the ion An atom or group of atoms that carries a positive or negative electric charge as a result of having lost or gained one or more electrons negatively-charged particles.
This lack of energy results in an increase in the sensitivity of NMDA receptors to glutamate molecules. Anti-glutamate therapies include drugs and supplements that are capable of reducing these various effects of glutamate in cells.
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