Central role of microglia in neonatal excitotoxic lesions ef the murine periventricular white matter

Periventricular leukomalacia (PVL) is the main cause of neurologic handicap in pre-term infants. The understanding of cellular and molecular mechanism s 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 pathw ay. We previously described a neonatal mouse model of excitotoxic white mat ter lesion mimicking human PVL. In the present study, we used this experime ntal tool to investigate the cellular populations and the glutamate recepto r subtypes involved in excitotoxic white matter lesions. Combined immunohis tochemical, electron microscopic, and cell death detection data revealed th at microglial activation and astrocytic death were the primary responses of white matter to excitotoxic insult. In vitro experiments suggested that mi croglia activated by ibotenate released soluble factors that kill astrocyte s. The use of selective agonists and antagonists of glutamate receptors rev ealed that N-methyl-D-aspartate (NMDA) receptor activation was essential an d sufficient to produce cystic white matter lesions. NMDA receptor immunohi stochemistry labeled microglial cells in the neonatal periventricular white matter. The developing white matter displayed a window of sensitivity to e xcitotoxic damage that was paralleled by the transient presence of NMDA rec eptor-expressing white matter cells. Assuming that similar pathophysiologic mechanisms are present in human pre-term infants, microglia and NMDA recep tors could represent key targets for treatment of PVL.