Glutamate is generally acknowledged to be the most important transmitter for normal brain function. Nearly all excitatory neurons in the central nervous system are glutamatergic, and it is estimated that over half of all brain synapses release this agent. Glutamate plays an especially important role in clinical neurology because elevated concentrations of extracellular glutamate, released as a result of neural injury, are toxic to neurons (Box B).

Box B

Excitotoxicity in Acute Neuronal Injury.

Glutamate is a nonessential amino acid that does not cross the blood-brain barrier and must be synthesized in neurons from local precursors. The most prevalent glutamate precursor in synaptic terminals is glutamine. Glutamine is released by glial cells and, once within presynaptic terminals, is metabolized to glutamate by the mitochondrial enzyme glutaminase (Figure 6.9). Glutamate can also be synthesized by transamination of 2-oxoglutarate, an intermediate of the tricarboxylic acid (TCA) cycle. Hence, some of the glucose metabolized by neurons can also be used for glutamate synthesis.

Figure 6.9

Glutamate synthesis and cycling between neurons and glia. The action of glutamate released into the synaptic cleft is terminated by uptake into neurons and surrounding glial cells via specific transporters. Within the nerve terminal, the glutamine released (more...)

Following its packaging into synaptic vesicles by a Mg²⁺/ATP-dependent transport process, glutamate-filled vesicles are ready to dock and be released from presynaptic sites. Glutamate is removed from the synaptic cleft by several high-affinity glutamate transporters present in both glial cells and presynaptic terminals. Glial cells contain the enzyme glutamine synthetase, which converts glutamate into glutamine; glutamine is then transported out of the glial cells and into nerve terminals. In this way, synaptic terminals cooperate with glial cells to maintain an adequate supply of the neurotransmitter. This overall sequence of events is referred to as the glutamate-glutamine cycle.