Elsevier

The Journal of Nutrition

Volume 130, Issue 4, April 2000, Pages 1007S-1015S
The Journal of Nutrition

Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology1

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Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic receptors with intrinsic cation permeable channels [N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate]. There are three groups of metabotropic, G protein–coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Glutamate is the most abundant amino acid in the diet. There is no evidence for brain damage in humans resulting from dietary glutamate. A kainate analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors, may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury. It may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's chorea. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Such compounds are undergoing testing in humans, but therapeutic efficacy has yet to be established. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis. J. Nutr. 130: 1007S–1015S, 2000.

Key words:

glutamate
excitotoxicity
domoate
neuroprotection
cerebral ischemia

Abbreviations used:

ALS
amyotrophic lateral sclerosis
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
BMAA
β-methylamino-L-alanine
BOAA
β-N-oxalylamino-L-alanine
β-ODAP
β-N-oxalyl-α,β-diaminopropionic acid
CA1, CA3
cellular zones of hippocampus (cornu ammonis)
GABA
γ-aminobutyric acid
EAAC1
neuronal glutamate and aspartate transporter in rat brain
EAAT1–5
excitatory amino acids transporters 1–5, clones from human brain
EC50
50% effective concentration
EM
electron microscopy
EPSP
excitatory postsynaptic potential
GLAST (also GLAST1)
rat glial glutamate and aspartate transporter
GLT (also GLT1)
rat glial glutamate transporter
GluR1–4
glutamate A-D peptide subunits of the AMPA receptor
mGluR
metabotropic glutamate receptors, mGluR1–8 (there are presently eight)
MK-801
dizocilpine
MND
motor neuron disease
NAAG
N-acetyl-aspartylglutamate
3-NPA
3-nitropropionic acid
NR1
NR2A,B,C,D, peptide subunits of the NMDA receptor
NMDA
N-methyl-D-aspartate
TGF-β
transforming growth factorβ

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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.