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Periventricular leukomalacia (PVL) is the main cause of neurologic handicap in pre-term infants. The understanding of cellular and molecular mechanisms leading to white matter damage is critical for development of innovative therapeutic strategies for PVL. The pathogenesis of PVL remains unclear but possibly involves glutamate excitotoxicity as an important molecular pathway. We previously described a neonatal mouse model of excitotoxic white matter lesion mimicking human PVL. In the present study, we used this experimental tool to investigate the cellular populations and the glutamate receptor subtypes involved in excitotoxic white matter lesions. Combined immunohistochemical, electron microscopic, and cell death detection data revealed that microglial activation and astrocytic death were the primary responses of white matter to excitotoxic insult. In vitro experiments suggested that microglia activated by ibotenate released soluble factors that kill astrocytes. The use of selective agonists and antagonists of glutamate receptors revealed that N-methyl-D-aspartate (NMDA) receptor activation was essential and sufficient to produce cystic white matter lesions. NMDA receptor immunohistochemistry labeled microglial cells in the neonatal periventricular white matter. The developing white matter displayed a window of sensitivity to excitotoxic damage that was paralleled by the transient presence of NMDA receptor-expressing white matter cells. Assuming that similar pathophysiologic mechanisms are present in human pre- term infants, microglia and NMDA receptors could represent key targets for treatment of PVL.