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Compartmentation of Brain Glutamate Metabolism in Neurons and Glia^{1 ,2}

Department of Pediatrics, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318

³To whom correspondence should be addressed.

	ABSTRACT

TOP ABSTRACT Neurotransmission: an overview The glutamate-glutamine cycle Problems of the glutamate... Summary and future directions REFERENCES

 
Intrasynaptic [glutamate] must be kept low in order to maximize the signal-to-noise ratio after the release of transmitter glutamate. This is accomplished by rapid uptake of glutamate into astrocytes, which convert glutamate into glutamine. The latter then is released to neurons, which, via mitochondrial glutaminase, form the glutamate that is used for neurotransmission. This pattern of metabolic compartmentation is the "glutamate-glutamine cycle." This model is subject to the following two important qualifications: 1) brain avidly oxidizes glutamate via aspartate aminotransferase; and 2) because almost no glutamate crosses from blood to brain, it must be synthesized in the central nervous system (CNS). The primary source of glutamate carbon is glucose, and a major source of glutamate nitrogen is the branched-chain amino acids, which are transported rapidly into the CNS. This arrangement accomplishes the following: 1) maintenance of low external [glutamate], thereby maximizing signal-to-noise ratio upon depolarization; 2) the replenishing of the neuronal glutamate pool; 3) the "trafficking" of glutamate through the extracellular fluid in a nonneuroactive form (glutamine); 4) the importation of amino groups from blood, thus maintaining brain nitrogen homeostasis; and 5) the oxidation of glutamate/glutamine, a process that confers an additional level of control in terms of the regulation of brain glutamate, aspartate and -aminobutyric acid.

KEY WORDS: • glutamate • glutamine • branched-chain amino acids • glucose • transport • metabolism • neuron • glia • brain

	Neurotransmission: an overview

TOP ABSTRACT Neurotransmission: an overview The glutamate-glutamine cycle Problems of the glutamate... Summary and future directions REFERENCES

 
Neurotransmitters, the essential "currency" for the transfer of information between neurons, are released from a presynaptic terminal into a synaptic cleft. The binding of a transmitter to postsynaptic receptors induces an ionic flux that depolarizes the neuron. Neurotransmitter binding also may cause metabolic changes such as the activation of second messenger systems.

Efficient neurotransmission must satisfy two requirements. The level of neurotransmitter in the synaptic cleft must be kept low in order to maximize the signal-to-noise ratio upon binding of fresh transmitter to its receptor. If glutamate is the transmitter, a low external level prevents the excessive excitation ("excitotoxicity") that can injure and even kill susceptible neurons (Coyle and Puttfarcken 1993 , Huang et al. 1997 , Meldrum 1994 , Szatkowski and Attwell 1994 ). The second requirement of efficient neurotransmission is the rapid replacement of a transmitter that is released from a presynaptic terminal. This process may involve either reuptake of the transmitter from the synapse or resynthesis of the transmitter within the presynaptic site. These two mechanisms can coexist within a single neuron.

	The glutamate-glutamine cycle

TOP ABSTRACT Neurotransmission: an overview The glutamate-glutamine cycle Problems of the glutamate... Summary and future directions REFERENCES

 
Glutamic acid is the main excitatory transmitter in the central nervous system (CNS)⁴ (Erecinska and Silver 1990 ). Three types of postsynaptic glutamate receptors have been identified on the basis of their binding affinities for prototypical ligands, i.e., the kainate, 2-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Glutamatergic neurons mediate many vital processes, including the encoding of information, the formation and retrieval of memories, spatial recognition and the maintenance of consciousness (McEntee and Crook 1993 ). As noted above, excessive excitation of glutamate receptors has been associated with the pathophysiology of hypoxic injury, hypoglycemia, stroke and epilepsy. A strong association exists between injury and excessive excitation of the NMDA receptor, which gates the entry into neurons of potentially toxic levels of Ca²⁺ (Kristian and Siesjo 1998 ).

The glutamate-glutamine cycle (Fig. 1 ) is central to our understanding of brain glutamate metabolism (Hertz 1979 , Norenberg and Martinez-Hernandez 1979 , Shank and Aprison 1977 ). The cycle "begins" with the release of glutamate, a Ca²⁺-dependent process that involves fusion of glutamate-containing presynaptic vesicles with the neuronal membrane (Fillenz 1995 ). The "prerelease" concentration of glutamate in the synapse is 2–5 µmol/L. However, this value can rise to as much as 50–100 µmol/L after depolarization.

View larger version (15K): [in this window] [in a new window]   Figure 1. Schematic of the glutamate-glutamine cycle. According to this formulation, glutamate released from presynaptic terminals is transported primarily to astrocytes, where it is converted to glutamine via the glutamine synthetase pathway. The glutamine is released back to the neurons, where glutamate is regenerated via phosphate-dependent glutaminase, a mitochondrial enzyme.

Postsynaptic neurons remove little glutamate from the synapse. There is active reuptake into presynaptic neurons, but this mechanism appears to be less important than astrocytic transport (Danbolt 1994 , Gegelashvili and Schousboe 1998 , Takahashi et al. 1997 ). The fact that the membrane potential of astrocytes is low relative to that of neurons (Erecinska and Silver 1990 ) favors efficient glutamate uptake via a sodium-dependent mechanism. Transgenic mice that lack the glial-specific transporter are particularly vulnerable to excitoxic injury (Tanaka et al. 1997 ).

Astrocytes could dispose of transported glutamate in two ways. They could export it to blood capillaries, which abut the astrocyte foot processes (Brightman and Cheng-Tao 1988 ). However, this strategy would result in a net loss of carbon and nitrogen from the system. An alternate approach would be to convert glutamate into another compound, preferably a nonneuroactive species. The latter could be released to neurons, which could derive glutamate from this parent compound. The advantage of this approach is that neuronal glutamate could be restored without the risk of trafficking the transmitter through extracellular fluid, where glutamate would cause neuronal depolarization and a chronically high signal-to-noise ratio.

The latter approach appears to have been favored by evolutionary processes. Astrocytes readily convert glutamate to glutamine via the glutamine synthetase pathway:

This microsomal pathway is abundant in astrocytes (Martinez-Hernandez et al. 1977 , Norenberg and Martinez-Hernandez 1979 ). Indeed, histochemical studies suggest that the glia are virtually the sole site for glutamine synthetase activity in brain (Martinez-Hernandez et al. 1977 , Norenberg and Martinez-Hernandez 1979 ). The ammonia that is consumed to generate glutamine can be derived either from the blood (Cooper et al. 1979 ) or from brain metabolism. Brain glutamine levels may increase so abruptly in hyperammonemic states that the glia may swell. Inhibiting glutamine synthetase ameliorates this swelling and improves neurologic outcome (Takahashi et al. 1991 ).

Neuronal glutamine uptake proceeds via both sodium-dependent and sodium-independent mechanisms (Ramaharobandro et al. 1982 , Schousboe et al. 1979 , Yudkoff et al. 1989 ). During depolarization, when internal [ATP] tends to fall, the uptake of glutamine into nerve endings is augmented concomitantly (Erecinska et al. 1990 , Yudkoff et al. 1989 ).

The predominant metabolic fate of the glutamine taken up into neurons is hydrolysis to glutamate and ammonia via the action of phosphate-dependent glutaminase:

Glutaminase is a mitochondrial enzyme. Inorganic phosphate, derived primarily from the hydrolysis of ATP, lowers the K_m for glutamine. As we showed in studies of [2-¹⁵N]glutamine metabolism in synaptosomes, the sudden energy consumption that accompanies depolarization also favors glutamine hydrolysis (Erecinska et al. 1990 , Yudkoff et al. 1989 ). Indeed, we found that not all glutamate that is derived from glutamine is utilized to replenish the transmitter pool. A portion of this glutamate can be oxidized in nerve endings, primarily via transamination to 2-oxo-glutarate via aspartate aminotransferase (Erecinska et al. 1990 , Yudkoff et al. 1989 ). Glutamine, therefore, is not simply a precursor to neuronal glutamate but a potential fuel, which, like glucose, supports neuronal energy requirements (Erecinska et al. 1988 ).

With the regeneration of glutamate from glutamine, the final limb of the glutamate-glutamine cycle (Fig. 1) is closed. The significance of the cycle to brain glutamate handling is that it promotes the following events: 1) the rapid removal of glutamate from the synapse, thereby maintaining a low signal-to-noise ratio when glutamate is released from nerve endings; 2) the conversion in astrocytes of glutamate to glutamine, a nonneuroactive compound which, in effect, serves as a "carrier" of glutamate back to neurons; 3) a mechanism for the regeneration of glutamate in the neuronal compartment; 4) the provision to neurons of a metabolic substrate, i.e., glutamine, that can be used as a potential fuel; and 5) a mechanism for the "buffering" of ammonia, a potentially neurotoxic species, via the glial glutamine synthetase pathway.

	Problems of the glutamate-glutamine cycle model

TOP ABSTRACT Neurotransmission: an overview The glutamate-glutamine cycle Problems of the glutamate... Summary and future directions REFERENCES

 
The brain oxidizes glutamate.

Like all physiologic models, the glutamate-glutamine cycle oversimplifies a complex reality. The model ignores the fact that the brain avidly oxidizes glutamate. Indeed, the rate of oxidation may be so robust that glutamate could theoretically substitute for glucose as a fuel (Erecinska et al. 1988 , Yu et al. 1982 ). The primary mechanism of glutamate oxidation appears to be the aspartate aminotransferase reaction:

The 2-oxo-glutarate generated via transamination then enters the tricarboxylic acid cycle, where it is oxidized. Although the aminotransferase is freely reversible, the equilibrium usually favors the production of aspartate (Erecinska et al. 1990 ).

Whether glial glutamate enters the oxidative or glutamine synthetase pathways depends upon the external [glutamate]. Thus, at low external [glutamate], the glutamine synthetase pathway is favored, but when [glutamate]_ext is high, oxidative processes are recruited, with considerable glutamate being consumed via astrocytic malic enzyme (McKenna et al. 1996 ).

Both neurons and astrocytes also can oxidize glutamate via glutamate dehydrogenase, potentially a major route for the entry of glutamate carbon into the tricarboxylic acid cycle. However, our studies with stable isotopes indicate that this pathway, although present in nerve endings, is quantitatively less significant than asparate aminotransferase (Yudkoff et al. 1991 ). This is true not only of flux in the direction of oxidative deamination (Glutamate 2-oxo-glutarate + NH₃), but also of flux in the reverse direction, i.e., the reductive amination of ketoglutarate (Yudkoff et al. 1991 ).

The concept of brain glutamate oxidation must be qualified. Glucose is the major metabolic fuel of the brain, at least in the basal state. [During starvation and attendant ketoacidosis, brain extracts blood acetoacetate and 3-OH-butyrate as major fuels (Gjedde and Crone 1975 , Owen et al. 1967 ).] Furthermore, there is little passage of either glutamate or glutamine across the blood-brain barrier (Grill et al. 1992 , Smith et al. 1987 ). Thus, neither amino acid could serve as a conventional metabolic substrate. However, both compounds are important to brain energy economy in the sense that the utilization of glucose as a fuel does not proceed as a simple metabolic sequence, i.e., glucose pyruvate acetyl-CoA tricarboxylic acid cycle. Instead, glucose carbon must pass through a relatively large (5–10 mmol/L) intracellular pool of glutamate and glutamine before its final oxidation:

It is uncertain to what extent the oxidation of glutamate or glutamine satisfies brain metabolic demands. However, in hypoglycemic states, the consumption of glutamate and glutamine increases (Erecinska et al. 1988 , Yudkoff et al. 1989 ). A similar pattern occurs during acidosis, when flux through glycolysis is curtailed, and astrocytes avidly consume both glutamate and glutamine (unpublished). The fact that astrocytes can use glutamine as a fuel deserves special emphasis. The glutamate-glutamine cycle implies a net release of glutamine by astrocytes, but these cells also can oxidize glutamine (Schousboe et al. 1979 , Yudkoff et al. 1988 ). They are capable of transporting this amino acid and, via phosphate-dependent glutaminase, reconverting it back to glutamate.

The significance of brain glutamate oxidation extends beyond the issue of energy requirements. Consumption of an amino acid implies another mechanism for control of its concentration. Oxidation of glutamate in astrocytes becomes most robust when the level of this amino acid is relatively high (McKenna et al. 1996 ). Thus, the disposal of glutamate by the glia is not the province of the glutamine synthetase pathway alone. Similarly, the inhibition of transamination in nerve endings, a treatment that also inhibits glutamate oxidation, is associated with a significant rise of the internal level of this amino acid (Erecinska et al. 1988 ).

The external source of nitrogen.

No organ exists in metabolic isolation from the rest of the body. Lost nutrients must be replenished. Brain therefore requires an external source of nitrogen to compensate for glutamate and glutamine lost to oxidation. There also may be a net efflux of glutamine from the CNS (Grill et al. 1992 ), perhaps representing a mechanism for the maintenance of overall metabolic balance.

Glucose carbon is the major source for the carbon of glutamate and glutamine. Glucose is well-suited to assume this role. It passes readily from blood to brain via specific transport systems. It is oxidized via the tricarboxylic acid cycle to 2-oxo-glutarate, which is transaminated to yield glutamic acid (Erecinska et al. 1988 ).

A problematic issue is the source of the amino groups of glutamate. Little if any glutamate crosses the blood-brain barrier. The obvious reason is that the passage of relatively large amounts of glutamate through the extracellular space of the brain would run a risk of causing a depolarization of susceptible neurons. Therefore, there must exist an alternate source of -NH₂ groups to support glutamic acid synthesis.

The branched-chain amino acids (leucine, isoleucine, valine) are plausible candidates for the role of N donors. They are transported rapidly across the blood-brain barrier (Oldendorf 1971 ). Leucine crosses more swiftly than any other amino acid (Smith et al. 1987 ). Furthermore, in many peripheral tissues, these compounds are major sources of glutamate N. Thus, skeletal muscle releases both alanine and glutamine, which then serve as gluconeogenic precursors in the liver and kidney, respectively (Harper et al. 1984 ). The branched-chain amino acids, particularly leucine, constitute a major source for the -NH₂ groups in these amino acids:

In addition, the brain has an abundant activity of branched-chain amino acid aminotransferase:

This enzyme is present in both cytosolic and mitochondrial isoforms with high activity in the glia (Bixel et al. 1997 , Hutson et al. 1992 ). A single gene product probably mediates the transamination of all three branched-chain amino acids, although the affinities of each may vary. Astrocytes figure prominently in the metabolism of the branched-chain amino acids and ketoacids (Auestad et al. 1991 , Bixel and Hamprecht 1994 , Hamprecht et al. 1995 ).

We explored the role of leucine as a nitrogen donor in glia by incubating cultured astrocytes with [¹⁵N]leucine and using gas chromatography-mass specrometry to measure ¹⁵N incorporation into glutamate and glutamine (Fig. 2 ) (Yudkoff et al. 1994 ). We found that at least 25–30% of the nitrogen of glutamate/glutamine was derived from leucine alone. It should be stressed that, in performing these studies, the incubation medium contained other amino acids, including many that theoretically would serve as alternate N donors. The cells therefore are presented with a "choice" of potential sources of amino groups. The fact that a single compound is preferentially employed for this purpose is impressive.

View larger version (20K): [in this window] [in a new window]   Figure 2. The metabolism of [15N]leucine in cultured astrocytes. Cells were incubated in a medium that contained [15N]leucine (0.1 mmol/L) as well as 15 unlabeled amino acids (0.1 mmol/L each) and NH4Cl (0.1 mmol/L). At the indicated times, the enrichment (atom % excess) was determined in [15N]leucine, [15N]isoleucine, [15N]valine and [2-15N]glutamine. These measurements were done with the use of gas chromatography-mass spectrometry. From Yudkoff et al. 1994 .

The branched-chain aminotransferase reaction is freely reversible and the parent amino acid is readily regenerated from the ketoacid:

We found that leucine is formed by astrocytes or synaptosomes when they are incubated with [¹⁵N]glutamate and 2-oxo-isocaproic acid (Yudkoff et al. 1996b ). However, additional studies revealed that the polarity of the system was different in neuronal vs. astrocytic systems. In astrocytes, the reaction tended to proceed in the "forward" direction, toward the transamination of leucine and the production of branched-chain ketoacid (Yudkoff et al. 1996b , Yudkoff 1997 ). In the neuronal system, the opposite was the case. Furthermore, we noted that astrocytes released almost all of the 2-oxo-isocaproic acid ("ketoleucine") that they formed from leucine to the incubation medium (Yudkoff et al. 1996a ).

This pattern of relationships suggested to us the possibility of a "leucine-glutamate cycle" (Fig. 3 ) that would function in tandem with the glutamate-glutamine cycle. According to this formulation, leucine entering brain from the periphery is transaminated to yield a ketoacid and glutamate. The latter would be converted to glutamine, which is released to neurons and there reconverted to glutamate in the glutamate-glutamine cycle. The ketoacid formed from leucine also would be released to the extracellular fluid and taken up by neurons. This ketoacid would become transaminated with glutamate to regenerate leucine, the parent amino acid. The latter then is transported back to astrocytes, thereby completing the second limb of the putative cycle.

View larger version (16K): [in this window] [in a new window]   Figure 3. A schematic of a putative model of brain leucine metabolism ("leucine-glutamate cycle"). According to this formulation, leucine from peripheral blood is rapidly transported into astrocytes, which transaminate leucine with 2-oxo-glutarate (2-KG) to form glutamate and 2-oxo-ketoisocaproate (KIC), the ketoacid of leucine. The glutamate is converted to glutamine via astrocytic glutamine synthetase. Glutamine is converted in neurons to glutamate (see Fig. 1 ). The KIC also is released to neurons, where it may become transaminated with glutamate to yield leucine. The latter is transported back to astrocytes, thereby completing a functional cycle.

The hypothetical leucine-glutamate cycle is but one mechanism for the importation of -NH₂ into the CNS. Peripheral branched-chain amino acids probably provide 30–50% of the requirement for amino groups. The remainder presumably derive from other sources, including those amino acids that readily cross the blood-brain barrier.

In addition to the importation of -NH₂, the brain also has a need to dispose of waste nitrogen. Brain synthesizes no urea. The release of glutamine to the periphery may provide one mechanism for the removal of excess N (Grill et al. 1992 ). Brain is capable of generating ammonia, whose production rises sharply during depolarization. As noted above, a portion of this ammonia probably represents enzymatic hydrolysis of glutamine via the phosphate-dependent glutaminase. A fraction also can derive from oxidative deamination in the glutamate dehydrogenase reaction, but the contribution of this pathway is relatively small (Yudkoff et al. 1991 ). Alternate routes of ammonia production, e.g., the purine nucleotide cycle, are present in the nervous system (Yudkoff et al. 1987 ), but their quantitative significance is uncertain.

	Summary and future directions

TOP ABSTRACT Neurotransmission: an overview The glutamate-glutamine cycle Problems of the glutamate... Summary and future directions REFERENCES

 
The most salient feature of brain glutamate handling is the exquisite anatomic compartmentation that accommodates the two main requirements of glutamatergic neurotransmission, i.e., maintenance of a relatively low external [glutamate] and replenishment of the internal neuronal glutamate pool. The metabolic stability that this compartmentation affords is remarkable when one considers that it is maintained during the countless cycles of depolarization and repolarization that characterize normal neurotransmission.

The study of brain glutamate metabolism is incomplete. An unsettled issue is the complete identification of the mechanisms that allow the system to adapt rapidly and effectively to abrupt changes of internal and external [glutamate]. The integrity of the glutamate metabolic system is ensured by numerous factors, e.g., hormones, ions, second messengers and other neurotransmitters. Little is understood about the relationship to development and maturation. It is unclear, for example, at what stage of neurodevelopment the various intercellular cycles appear or whether the anatomic compartmentation serves a trophic role in brain development.

An equally important question is the effect of disease states on brain glutamate metabolism. Hyperammonemia, for example, has been associated with an acute rise of intra-astrocytic glutamine which, if sufficiently great, can lead to frank cell swelling (see above). Inhibition of glutamine synthetase can attenuate this process and improve overall outcome in experimental models of ammonia poisoning. In maple syrup urine disease, there occurs a congenital deficiency of branched-chain ketoacid dehydrogenase. The result is an extreme rise of branched-chain ketoacids in the brain and peripheral tissues. As a consequence, the equilibrium of branched-chain amino acid transaminase is shifted toward the synthesis of branched-chain amino acids with a concomitant consumption of glutamate and glutamine. Unless treatment is promptly instituted, affected patients may suffer progressive neurologic deterioration and even irreversible brain damage. It is not certain that the symptomatology is attributable to a depletion of brain glutamate and glutamine, but it is probably of clinical significance that analysis of amino acids in the spinal fluid during periods of clinical decompensation reveal a sharp diminution in the concentration of these amino acids (Sansaricq et al. 1989 ).

	FOOTNOTES

 
¹ Presented at the International Symposium on Glutamate, October 12–14, 1998 at the Clinical Center for Rare Diseases Aldo e Cele Daccó, Mario Negri Institute for Pharmacological Research, Bergamo, Italy. The symposium was sponsored jointly by the Baylor College of Medicine, the Center for Nutrition at the University of Pittsburgh School of Medicine, the Monell Chemical Senses Center, the International Union of Food Science and Technology, and the Center for Human Nutrition; financial support was provided by the International Glutamate Technical Committee. The proceedings of the symposium are published as a supplement to The Journal of Nutrition. Editors for the symposium publication were John D. Fernstrom, the University of Pittsburgh School of Medicine, and Silvio Garattini, the Mario Negri Institute for Pharmacological Research.

² Supported by National Institutes of Health grants NS37915, HD26979 and NS34900 and by the W. T. Grant Foundation.

⁴ Abbreviations used: AMPA, 2-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid; CNS, central nervous system; NMDA, N-methyl-D-aspartate.

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