Elsevier

Progress in Neurobiology

Volume 65, Issue 1, September 2001, Pages 1-105
Progress in Neurobiology

Glutamate uptake

https://doi.org/10.1016/S0301-0082(00)00067-8Get rights and content

Abstract

Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.

Introduction

As is apparent from the publications cited in this review, glutamate and glutamate transporters are somehow involved in most aspects of normal and abnormal brain function as well as in the function of a number of peripheral organs. It is therefore not surprising that the literature on glutamate uptake and on glutamate in general is growing at an increasing rate. Even though the number of publications on glutamate uptake is low compared to the total number of publications on glutamate receptors, metabolism, pharmacology and toxicology, there are too many publications on glutamate transporters alone to cite them all. Most of the older publications are therefore left out. I even fear that some important newer publications may have escaped my attention and I apologize to the authors for that.

Because the roles of the glutamate transporters cannot be understood unless they are seen in a wider context, I have included information on glutamatergic neurotransmission and glutamate metabolism in general in order to help the non-expert reader. This, however, dramatically increases the number of relevant publications. The non-transporter publications cited here therefore represent only examples.

The amino acid l-glutamate (Fig. 6) is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is probably involved in most aspects of normal brain function including cognition, memory and learning (for review, see Fonnum, 1984, Ottersen and Storm-Mathisen, 1984, Collingridge and Lester, 1989, Headley and Grillner, 1990). Glutamate also plays major roles in the development of the central nervous system, including synapse induction and elimination, and cell migration, differentiation and death (1see Section 9.7.1). Most neurons, and even glial cells have glutamate receptors in their plasma membranes (Hösli and Hösli, 1993, Steinhauser and Gallo, 1996, Vernadakis, 1996, Conti et al., 1999, Shelton and McCarthy, 1999, Bergles et al., 2000). Further, glutamate plays a signaling role also in peripheral organs and tissues (see Section 10) as well as in endocrine cells (for review see, Moriyama et al., 2000).

The brain contains huge amounts of glutamate (about 5–15 mmol per kg wet weight depending on the region) (for references, see Schousboe, 1981), but only a tiny fraction of this glutamate is normally present extracellularly (outside or between the cells). The concentrations in the extracellular fluid (which represents 13–22% of brain tissue volume; see Section 3.2.1 for references) and in the cerebrospinal fluid (CSF) are normally around 3–4 μM and around 10 μM, respectively (Hamberger et al., 1983, Lehmann et al., 1983, Hamberger and Nyström, 1984). Consequently, the concentration gradient of glutamate across the plasma membranes is several thousand-fold. The highest concentrations are found inside nerve terminals (Ottersen et al., 1992, Storm-Mathisen et al., 1992, Ottersen et al., 1996; see also Section 3.2.2.4).

It should be noted that the distribution of glutamate is in a dynamic equilibrium which is highly sensitive to changes in the energy supply. Firstly, glutamate will leak out of the cells if the cells run out of energy (see 5.1 The uptake mechanism and the stoichiometry of the process, 12.1.5 Glutamate release may start vicious circles, 12.3.1 Glutamate uptake in ischemia). Secondly, there is a rapid turnover of glutamate. Glutamate is continuously being released from cells and is continuously being removed from the extracellular fluid (see 1.1.3 Glutamate uptake removes glutamate from the extracellular fluid, 3.2.2 Glutamate release).

Glutamate exerts its signaling role by acting on glutamate receptors. These receptors are located on the surface of the cells expressing them. Therefore it is the glutamate concentration in the surrounding extracellular fluid that determines the extent of receptor stimulation. It is of critical importance that the extracellular glutamate concentration is kept low. This is required for a high signal-to-noise (background) ratio in synaptic as well as in extrasynaptic transmission. Further, excessive activation of glutamate receptors is harmful, and glutamate is thereby toxic in high concentrations (see Section 12.1). Thirdly, for economic reasons it is necessary to conserve the glutamate released.

In contrast, intracellular glutamate is generally considered non-toxic, but it should be kept in mind that intracellular glutamate may not be completely inert. Glutamate may serve as an intracellular messenger in pancreatic β-cells (although this is controversial; see Section 10.4) and seems to participate in the regulation of the cell surface expression of glutamate transporters (see Section 11.3.2).

Glutamate must be removed from the entire extracellular space because glutamate receptors are found on most of the cellular elements (dendrites, nerve terminals, neuronal cell bodies as well as glial cells; see Section 3.2.1). Thus, it is not only a question of keeping a low resting concentration inside the synaptic clefts, but also outside the clefts (extrasynaptically). (The synaptic clefts are in continuity with the general extracellular space in the brain; see Fig. 3, Fig. 4, Fig. 14.)

There does not seem to be any enzyme extracellularly that can metabolize glutamate to any significant degree. Consequently, the only rapid way to remove glutamate from the extracellular fluid surrounding the receptors is by cellular uptake (Balcar and Johnston, 1972b, Logan and Snyder, 1972, Johnston, 1981). Although simple diffusion appears to be an important mechanism for glutamate removal from the synaptic clefts on the submillisecond timescale (see Section 3.2.2), at least at synapses with small diameters (Fig. 3A), diffusion can only work quickly over very short distances (a few hundred nanometers) and it can only be an efficient synaptic removal mechanism as long as the glutamate concentration in the extracellular fluid outside synapses is kept low. It follows that the leak of glutamate out of the brain tissue and into the cerebrospinal fluid is a process which is far too slow to maintain low extracellular levels around synapses because of the tissue thickness (tens of millimeters in humans).

Consequently, glutamate uptake is the mechanism responsible for the long-term maintenance of low extracellular concentrations of glutamate (see Section 3). Glutamate uptake is accomplished by means of glutamate transporter proteins (see 2 Glutamate transporter types: an overview, 4 Sodium- and potassium-coupled glutamate transporters) which use the electrochemical gradients across the plasma membranes as driving forces for uptake (see Section 5). Both neurons and glial cells express glutamate transporters (see 4.2 Does a nerve terminal glutamate transporter exist?, 9 Localization of glutamate transporters). Because of the high rates of glutamate release, inhibition of glutamate uptake leads to high extracellular levels of glutamate within seconds (Jabaudon et al., 1999; see Section 3.2.2).

This relatively simple role of glutamate uptake is generally agreed upon. The current debate concerns the roles of glutamate transporters in disease (see Section 12) and their more subtle effects on neurotransmission (see Section 3.2). They may modify synaptic and extrasynaptic transmission partly by influencing glutamate diffusion (see Section 3.2), partly by their associated anion channel activities (see Section 5.2) and partly because the transport process is electrogenic (see Section 5.1). In fact, glutamate uptake can cause depolarization (McMahon et al., 1989, Frenguelli et al., 1991) by influx of Na+ ions, which has been suggested to be used in the control of hormone secretion in GH3 pituitary cells (Villalobos and Garcı́a-Sancho, 1995). Further, glutamate uptake may play a role in the reported requirement of astrocytes for oscillatory activity in neurons (Verderio et al., 1999).

Glutamate taken up by cells may be used for metabolic purposes (protein synthesis, energy metabolism, ammonia fixation) or be reused as transmitter.

In nerve terminals, reuse as transmitter is straightforward. Glutamate is transported into synaptic vesicles by a vesicular glutamate transporter (see Section 2.2.2; Fig. 1, Fig. 2) and subsequently released by exocytosis (for review, see Südhof, 1995, Augustine et al., 1996, Ludger and Galli, 1998, Cousin and Robinson, 1999). It seems plausible that glutamate is also released, at least to some extent, directly from cytosol (non-vesicularly) through plasma membrane proteins (see Section 3.2.2).

In astrocytes, glutamate taken up from the extracellular fluid may be converted to glutamine which is released to the extracellular fluid, taken up by neurons and reconverted to glutamate inside neurons (Fig. 1). This trafficking of glutamate and glutamine between astrocytes and neurons has been proposed to be a major pathway by which transmitter glutamate is recycled. It is commonly referred to as the glutamine–glutamate cycle. This concept of a compartmentation of glutamate into two pools was introduced in the early seventies (Van den Berg and Garfinkel, 1971) and the notion of a predominant glial synthesis of glutamine a little later when glutamine synthetase was shown immunocytochemically to be a glial enzyme (Martinez-Hernandez et al., 1977; for review, see Erecinska and Silver, 1990, Westergaard et al., 1995, Ottersen et al., 1996).

Glutamine is normally present in the extracellular fluid at around 200–500 μM (Gjessing et al., 1972, Hamberger et al., 1983, Hamberger and Nyström, 1984). This does not compromise neurotransmission because glutamine is, in contrast to glutamate, non-toxic and does not activate glutamate receptors.

The above description of glutamate and glutamine metabolism represents an oversimplification (for review, see Fonnum, 1993, Westergaard et al., 1995, Broman et al., 2000). It will be clear from the discussion below that transmitter glutamate is not necessarily derived from glutamine, nor is transmitter glutamate necessarily converted into glutamine after uptake into astrocytes, nor does glutamine necessarily act as a precursor for transmitter glutamate, but may serve as a nutrient for neurons. Further, it is still not known how large the neuronal glutamate uptake activity is in relation to glial glutamate uptake activity (see Section 9.1.1).

After uptake into astrocytes, glutamate may be metabolized through two different pathways: (a) It may be amidated to glutamine by the ATP-dependent, glia-specific enzyme glutamine synthetase (Martinez-Hernandez et al., 1977, Ottersen et al., 1992, Laake et al., 1995), or (b) it may be converted to α-ketoglutarate (through deamination by glutamate dehydrogenase or by transamination by one of the transaminases). Alfa-ketoglutarate may be metabolized through the tricarboxylic acid cycle to succinate, fumarate and malate, successively. Malate may be metabolized further through the tricarboxylic acid cycle, or it may be decarboxylated to pyruvate and reduced to lactate. The latter pathway has been demonstrated in vitro (McKenna et al., 1996) and it was inferred from in vivo data (Hassel and Sonnewald, 1995). Both glutamine and lactate are exported from astrocytes to the extracellular fluid from which they may enter neurons.

An important precursor role of glutamine for transmitter glutamate has been demonstrated in vitro (Hamberger et al., 1979), but the in vivo evidence is less convincing; glutamine administered to the intact brain is mostly metabolized to CO2 (Zielke et al., 1998), in agreement with an important role for glutamine as a neuronal energy substrate (Bradford et al., 1978, Hassel et al., 1995). Further, some populations of glutamatergic neurons do not express phosphate activated glutaminase (Ottersen et al., 1998, Laake et al., 1999), the mitochondrial enzyme that deamidates glutamine to glutamate (for review, see Kvamme et al., 1988). Therefore, the role of glutamine as a transmitter precursor may be somewhat overestimated (for review, see Fonnum, 1993, Broman et al., 2000). Recently glutamine-independent formation of transmitter glutamate was reported (Hassel and Bråthe, 2000b). The ability of glutamatergic neurons to sustain release of glutamate independently of glutamine is related to their newly found capacity for pyruvate carboxylation (Hassel and Bråthe, 2000a, Hassel and Bråthe, 2000b). Pyruvate carboxylation replenishes the loss of α-ketoglutarate from the tricarboxylic acid cycle that is inherent in release of glutamate. The synthesis of glutamate requires an amino group, and it is at present not clear where this amino group comes from. One possibility is that other amino acids (alanine, leucine or isoleucine) which may be imported from glia, other neurons or from the circulation, donate their amino groups through transamination reactions. Another possibility is that glutamate is formed from α-ketoglutarate and ammonia through the action of glutamate dehydrogenase. The ammonia needed for this pathway could be obtained through any deamination reaction, e.g. the glutaminase reactions within the neuron itself, or it could be derived from the circulation. Glutamate dehydrogenase has been detected in nerve terminals (McKenna et al., 2000). Therefore, glutamatergic neurons may not be as dependent on astrocytes for the supply of precursors for transmitter glutamate as previously thought, and this applies to both the carbon chain (i.e. α-ketoglutarate) and the amino group of the glutamate molecule.

Glutamine is a substrate for a number of transporters (the sodium-dependent system A, ASC and N transporters as well as the sodium-independent system l transporter). The export of glutamine from astrocytes to the extracellular fluid appears to be mediated through a recently cloned system N glutamine transporter SN1 (=NAT) (Chaudhry et al., 1999, Gu et al., 2000; J.-L. Boulland, F.A. Chaudhry, K.K. Osen, L.M. Levy, N.C. Danbolt, R.H. Edwards and J. Storm-Mathisen, unpublished data) and possibly also through the AST2 amino acid transporter (Bröer et al., 1999), but AST2 is expressed at low levels in the brain. Neurons take up glutamine from the extracellular fluid by specific glutamine transporters, probably including the recently cloned system A transporters GlnT (=SAT1) (Varoqui et al., 2000) and SAT2 (=ATA2=SA1) (Reimer et al., 2000, Sugawara et al., 2000, Yao et al., 2000) which are abundantly expressed on glutamatergic neurons throughout the CNS.

Astrocytic export and neuronal uptake of lactate occurs through different monocarboxylate transporters, several of which have recently been cloned (for review, see Halestrap and Price, 1999).

Three different families of glutamate receptor proteins have been identified with molecular cloning (for review, see Hollmann and Heinemann, 1994, Schoepfer et al., 1994, Borges and Dingledine, 1998, Nakanishi et al., 1998, Ozawa et al., 1998, Dingledine et al., 1999). One family of glutamate receptors is activated by the glutamate analogue N-methyl-d-aspartate (NMDA) and these receptors (NR1, NR2A, NR2B, NR2C and NR2D) are collectively referred to as NMDA-receptors. Another family of receptors is activated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and by kainate (Fig. 6). According to their preference for AMPA or kainate, these receptors are further subdivided into AMPA-receptors (GluR1–4) and kainate receptors (GluR5–9, KA1 and KA2). The NMDA and AMPA/kainate receptors are all glutamate gated ion channels (conducting only Na+ or both Na+ and Ca2+) and are collectively referred to as ionotropic glutamate receptors. The AMPA receptors open readily upon glutamate exposure, but desensitize quickly (Tang et al., 1989, Trussell and Fischbach, 1989) and are of low affinity (Patneau and Mayer, 1990). The desensitization can be blocked by adding cyclothiazide (Trussell et al., 1993). In contrast, the NMDA receptors have much higher affinities and are slowly inactivating. To be activated they need both glutamate binding and an already depolarized membrane.

The third family of glutamate receptors consists of G-protein coupled receptors, the so-called metabotropic receptors (mGluR1–8) which are subdivided into groups I (mGluR1 and mGluR5), II (mGluR2 and mGluR3) and III (mGluR4, mGluR6, mGluR7 and mGluR8). The receptors in groups I and II are activated by (±)1-amino-cyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) while group III receptors are activated by l(+)-2-amino-4-phosphonobutyric acid (l-AP4). Group I receptors are coupled to phospholipase C and thereby to inositol triphosphate and diacylglycerol production, whereas groups II and III are negatively coupled to adenylate cyclase.

Finally, the so-called delta (glutamate) receptors should be mentioned. These proteins display a low, but significant sequence identity to ionotropic glutamate receptors and are therefore believed to be receptors, but no function has as yet been assigned to them. Further, no agonist activating them has so far been found (for references, see Mayat et al., 1995, Kurihara et al., 1997, Zhao et al., 1997, Hirai, 2000). They will not be discussed further in this review.

An impressive amount of data has been published on the localizations and densities of glutamate receptor proteins and their splice variants as well as their mRNAs, but a description of receptor localization is beyond the scope of this review (e.g. for short reviews, see Forsythe and Barnes-Davies, 1997, Takumi et al., 1998, Wenthold and Roche, 1998, Petralia et al., 1999).

It was noted already 65 years ago that glutamate plays a central metabolic role in the brain (Krebs, 1935) and that brain tissue has a very high glutamate uptake activity (Stern et al., 1949). The excitatory action of glutamate on brain tissue was discovered in 1954 (Hayashi, 1954, Curtis et al., 1959, Curtis et al., 1960) and the complex compartmentalization of the glutamate–glutamine metabolism soon afterwards (Berl et al., 1961, Berl et al., 1962, Van den Berg and Garfinkel, 1971, Balcar and Johnston, 1975). These findings led to the understanding that glutamate uptake is important in controlling the excitatory action of glutamate (Logan and Snyder, 1971, Logan and Snyder, 1972, Wofsey et al., 1971, Balcar and Johnston, 1972b) and scientists started to wonder if glutamate, an amino acid with multiple ‘ordinary’ metabolic roles, actually could be the major excitatory neurotransmitter in the mammalian nervous system (for review, see Johnston, 1981, Roberts et al., 1981, Schousboe, 1981, Watkins and Evans, 1981, Fonnum, 1984). Aided by the synthesis of a number of different glutamate and aspartate analogues, four different types of glutamate receptors were identified (for review, see Sharif, 1985, Mayer and Westbrook, 1987, Collingridge and Lester, 1989, Monaghan et al., 1989, Hansen and Krogsgaard-Larsen, 1990). The receptors were classified as NMDA receptors, quisqualate receptors (later renamed to AMPA receptors), kainate receptors and l-AP4 receptors (later renamed to metabotropic receptors). When the first glutamate receptors were cloned in 1989 and in the early 1990s, it was found that these four pharmacologically identified receptor types correspond to the three protein families described above (see Section 1.2), namely NMDA receptors, AMPA/kainate receptors and metabotropic receptors.

During the 1970s and 1980s, a number of groups studied the properties of the glutamate uptake system and showed that the uptake process is electrogenic and driven by the ion gradients of K+ and Na+ (for review, see Fonnum, 1984, Kanner and Schuldiner, 1987, Nicholls and Attwell, 1990). Glutamate uptake was found to be present both in glial cells (for review, see Schousboe, 1981) and in neurons (for review, see Storm-Mathisen, 1977b, Storm-Mathisen, 1981). After the purification (Danbolt et al., 1990) and cloning of the first three glutamate transporters (Kanai and Hediger, 1992, Pines et al., 1992, Storck et al., 1992, Tanaka, 1993b), it became clear that the glutamate uptake system is far more complex than would be expected for a simple glutamate drainage system (for review, see Kanai et al., 1993, Danbolt, 1994, Gegelashvili and Schousboe, 1997, Kanai et al., 1997, Robinson and Dowd, 1997, Beckman and Quick, 1998, Danbolt et al., 1998b, Bergles et al., 1999, Hediger, 1999, Kullmann, 1999, Seal and Amara, 1999, Sims and Robinson, 1999, Danbolt, 2000) and a role in the modulation of synaptic transmission was suggested. As will be outlined below, the roles of glutamate transporters in synaptic transmission are far from being understood.

Section snippets

Glutamate transporter types: an overview

Cells in the brain express a number of different proteins able to transport glutamate. Some of these are found in the plasma membranes and some are found intracellularly.

Maintenance of low extracellular levels of glutamate

Considering the huge amounts of glutamate in the brain (see Section 1.1.1) and the importance of controlling the extracellular concentrations of glutamate (see 1.1.2 The extracellular concentrations of glutamate must be controlled, 12.1 The toxicity of glutamate), it is logical that the brain has powerful protective systems. Because there is no (or at least negligible) extracellular conversion of glutamate (see Section 1.1.3), brain tissue needs a very high glutamate uptake activity to protect

Glutamate transporters identified by molecular cloning

Five different ‘high-affinity’ glutamate (excitatory amino acid) transporters have been cloned so far (for review, see Saier, 1999, Slotboom et al., 1999b): GLAST (EAAT1) (Storck et al., 1992, Tanaka, 1993b), GLT (EAAT2) (Pines et al., 1992), EAAC (EAAT3) (Kanai and Hediger, 1992), EAAT4 (Fairman et al., 1995) and EAAT5 (Arriza et al., 1997). The actual meanings of the acronyms (GLAST, glutamate–aspartate transporter; GLT, glutamate transporter; EAAC, excitatory amino acid carrier; EAAT,

Mechanism of glutamate uptake

Our basic knowledge about the transport mechanism and pharmacology of these transport systems originates from studies on crude preparations such as brain slices, crude homogenates, synaptosomes (pinched off nerve endings), cell cultures, etc. (for review, see Kanner and Schuldiner, 1987). The main conclusions of these studies have been confirmed with more refined techniques such as reconstitution of purified transporters in artificial membranes (e.g. Kanner and Sharon, 1978b, Gordon and Kanner,

Glutamate uptake is heterogenous, but differs from that of other neurotransmitters

Early studies of sodium-dependent neurotransmitter uptake in crude preparations such as brain slices and homogenates (Logan and Snyder, 1971, Logan and Snyder, 1972, Balcar and Johnston, 1972b) showed that the uptake of glutamate is completely independent of the uptake systems for glutamine, glycine, GABA, taurine, serotonin, catecholamines, dicarboxylates (glutarate, succinate, etc.) as well as all other neutral and basic amino acids tested. Although these observations imply a high degree of

Purification of GLT

To isolate a membrane protein, it is necessary to solubilize the protein of interest so that attachments to other structures are broken. Then a suitable method must be found for the separation of the protein of interest from the rest of the tissue components. But in order to monitor the purification process and find out if a separation has been achieved, it is imperative to be able to detect the protein. In the mid 1980s when the work was started to isolate a glutamate transporter, the

Molecular structure of glutamate transporters

The glutamate transporters are not only able to catalyze the influx of one glutamate, one proton and three Na+ in the exchange of one K+ (see Section 5.1), but they are also ion-channels (see Section 5.2). In addition to this, their functions can be modulated (see Section 11.3). To find out how this is possible, several investigators are working to determine the structure of these molecules.

Localization of glutamate transporters

Since the first antibodies and oligonucleotide probes to glutamate transporters became available from 1991 onwards, a substantial amount of knowledge has accumulated on the localizations of the transporter proteins.

Glutamate uptake in peripheral organs and tissues

Most cells and tissues have the ability to take up glutamate (for review, see Lerner, 1987). Some examples: sodium-dependent glutamate uptake systems have been identified in fibroblasts from various tissues (Balcar, 1992, Balcar et al., 1994, Cooper et al., 1998), in erythrocytes (Fujise et al., 1995, Ogawa et al., 1998, Sato et al., 2000), in macrophages (depending on differentiation stage and stimulation by cytokines: Rimaniol et al., 2000) platelets (Mangano and Schwarcz, 1981a, Mangano and

Regulation of glutamate uptake

It has been known for about two decades that brain glutamate uptake activity is not constant, but subject to regulation, not only during development (see Section 9.7.2), but also in the adult brain. A number of reports have been published on the regulation of glutamate uptake, especially during the last 5 years. It appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing (see 4.1 Glutamate transporters identified by molecular cloning, 12.3.2.2 Excitotoxic

Roles of glutamate transporters in disease

Most of the numerous studies on the role of glutamate in disease focus on glutamate receptors, release mechanisms and metabolism as well as on non-glutamatergic strategies to protect brain cells against glutamatergic overstimulation (e.g. glutamate receptor antagonists and sodium-channel blockers). Only a limited number of studies describe the glutamate transporters. Because the roles of the transporters are so intimately connected with the actions of glutamate, this section will start with a

Concluding remarks

Because glutamate uptake is the only (significant) glutamate removal mechanism, it is (at least on time scales longer than 1 ms) a major determinant of the spatiotemporal concentration profile of glutamate in the extracellular space following glutamate release and thereby a major determinant of glutamate receptor activation. Although our understanding of the glutamate uptake system is still incomplete, the emerging picture is that of a highly complex and sophisticated system for the control of

Acknowledgements

I would like to thank David Attwell, Wendy A. Fairman, Bjørnar Hassel, Dimitri Kullmann, Line M. Levy, Ole Petter Ottersen, Jon Storm-Mathisen and Kyrre Ullensvang for discussions and for critical reading of parts of the manuscript, and Gunnar F. Lothe, Carina Knudsen and Kari Ruud for help with the preparation of the illustrations. This work was supported by the Norwegian Research Council.

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