ULTRASTRUCTURE OF EXCITOTOXIC NEURONAL DEATH IN MURINE CORTICAL CULTURE

Ischemic and traumatic brain injury are likely to involve neuronal inj ury triggered by glutamate receptor overactivation. Although excitotox ic neuronal injury has been widely studied in the setting of primary c ulture, the extent to which these in vitro injury paradigms resemble i n vivo ischemic injury morphologically has not previously been well st udied. We studied glutamate receptor mediated neuronal death by transm ission electron microscopy and light microscopy. Morphologic character istics of neurons injured by 10 min exposure to 500 mu M glutamate inc lude rapid swelling of mitochondria and endoplasmic reticulum, and cyt oplasmic and nuclear lucency. Both alpha-amino-3-hydroxy-5-methyl-4-is oxazole propionic acid and kainic acid caused vacuolation, dilatation of the endoplasmic reticulum, cytoplasmic condensation and random cond ensation of chromatin with preserved mitochondria. None of these injur ies was ameliorated by cycloheximide or actinomycin D; all were signif icantly lessened by aurintricarboxylic acid. Gel electrophoresis showe d no increase in DNA fragmentation over control. The morphologic chang es seen with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and kainate are distinct from the changes induced by glutamate. Excit otoxic injury in this system due to high concentrations of glutamate r esembles necrosis while the other agonists produce a different form of cell death which is neither necrosis nor apoptosis.