It took, however, a long time to realize that. In fact, glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. The highest concentrations of glutamate are found in synaptic vesicles in nerve terminals from where it can be released by exocytosis. Further, the blood–brain barrier shields the brain from glutamate in the blood. Powerful uptake systems (glutamate transporters) prevent excessive activation of these receptors by continuously removing glutamate from the extracellular fluid in the brain. This effect is due to glutamate receptors present on the surface of brain cells. Considering this, it was a surprise to discover that glutamate has excitatory effects on nerve cells, and that it can excite cells to their death in a process now referred to as “excitotoxicity”. Glutamate is the most abundant free amino acid in the brain and is at the crossroad between multiple metabolic pathways.
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