Glutamate

The major EAA neurotransmitter in the CNS is L-Glu. (Note that all amino acids with the exception of glycine mentioned in this chapter are considered to be in the “L” configuration; thus, the “L” will be omitted, unless specifically indicated as “D” ). Early studies in invertebrates demonstrated the potent actions of the acidic amino acid Glu, as well as another acidic amino acid, Asp. Acceptance of Glu as a neurotransmitter in the CNS was delayed for many years as neuroscientists attempted to distinguish its role as a component of protein and peptides (e.g., glutathione), an important intermediate in numerous metabolic processes, and as a precursor to the inhibitory neurotransmitter GABA. Whereas Glu is found in all cells within the CNS, an unequal distribution of this amino acid as well as of Asp has been demonstrated.
Glutamate is synthesized in the CNS via the transamination of α-ketoglutarate, which is produced from glucose in the Krebs cycle. Additionally, Glu can be synthesized from glutamine via glutaminase. Once produced, Glu can be stored in vesicles. With the vast number of compounds that can feed into the Krebs cycle and the various sources of glucose, it is not surprising that the control of Glu synthesis in the CNS is still poorly understood.

The oral ingestion of Glu in protein, as the individual amino acid in the form of a dietary supplement or in the form of the flavor enhancer monosodium glutamate (MSG), fails to significantly increase CNS levels of this amino acid neurotransmitter. Following its ingestion, blood Glu levels do increase transiently, but largely because of the ability of the blood-brain barrier to regulate the entry of Glu into the CNS, no significant changes in brain Glu are observed. This ability to regulate synaptic Glu levels in brain despite fluctuations in peripheral levels is very important, because uncontrolled variations in CNS Glu would lead to serious consequences, ranging between seizures and coma for increases and decreases of Glu, respectively. Within the blood-brain barrier, there exists transport proteins that are responsible for controlling the influx of amino acids into the CNS. Of the three major types—acidic, basic, and neutral amino acid transporters—it is the acidic amino acid transporter that carries Glu. These transporters act via facilitated diffusion and cannot operate against a concentration gradient (active transport).
In actuality, the acidic amino acid transporter normally functions to move Glu out of the CNS. There have been studies in which Glu, often in the form of MSG, has been injected subcutaneously to neonatal mice or nonhuman primates and hypothalamic lesions noted. The lesions are mostly restricted to the circumventricular organs (those near the fourth ventricle), where the blood-brain barrier is significantly diminished. Additionally, when MSG is directly injected into the brains of laboratory animals, cellular necrosis is observed. When MSG is given in very high doses orally, however, the homeostatic processes in liver and other tissues help to regulate plasma Glu concentrations, and large changes are not observed. Additionally, the blood-brain barrier functions to keep CNS Glu at appropriate levels. The studies in which Glu is injected do not reflect the chemical changes that occur following oral ingestion and should not be interpreted as an indicator of toxicity of MSG.