Anatomy and physiology of glutamate in the CNS

Glutamate is the predominant excitatory neurotransmitter in the mammalian CNS. The neurotransmitter pool of glutamate is stored in synaptic vesicles and, upon depolarization, is released into the synaptic cleft in a Ca(2+)-dependent fashion. Glutamate is cleared from the synaptic cleft by high-affinity, Na(+)-dependent uptake carriers located in both neurons and glia. Glutamate acts on several distinct families of receptors, each of which has multiple subtypes with distinct pharmacologic and physiologic properties. Under some conditions, glutamate and related compounds act as excitotoxins and might participate in the events leading to neuronal damage and death in a variety of acute and chronic neurologic disorders. The potential for glutamate to become an excitotoxin is highly dependent upon neuronal metabolic status. A great deal of interest in developing selective, well-tolerated glutamate receptor antagonists for the treatment of a variety of neurologic disorders exists.