Synapse Development and Excitotoxicity

Excitotoxicity has emerged as an important mechanism of injury in the brain, and the concept is important for understanding perinatal brain pathology. Following the original observation by Lucas and Newhouse in 1957 that glutamate can damage the retina (31), Olney described the excitotoxicity concept in the 1970s as neuronal death mediated by excessive stimulation of excitatory amino acid receptors at synapses (54). The initial description of this concept in the central nervous system was based on the observation that the food additive monosodium glutamate caused selective hypothalamic lesions and obesity when fed to neonatal mice (54). Glutamate is the predominant excitatory amino acid neurotransmitter in the brain, and most neurons and many glia possess extracellular receptors for glutamate. Neuronal pathways that utilize glutamate as their neurotransmitter are ubiquitous in the brain, mediating vision, hearing, somatosensory function, learning and memory and other functions. Cell death in these disorders is mediated by excessive activation of the multiple receptor subtypes that recognize the various conformations of glutamate, leading in turn to calcium flooding and downstream toxic effects on cellular metabolism (7, 61).