The cerebellum has been shown to be vulnerable to global ischemic damage in tightly controlled zones of Purkinje cells (PCs) that lack aldolase C, an enzyme critical for glycolysis. Here, we investigated whether aldolase C-negative PCs were more likely to die after cerebral trauma in vivo, and whether this death was mediated by excitotoxic [alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-mediated] means in vitro. Mice were subjected to controlled cortical impact, or remained uninjured, and were killed at 6 h, 24 h or 7 days after injury. Cerebellar sections (both ipsilateral and contralateral to the site of cerebral injury) were stained against aldolase C and calbindin (a marker of PCs). The number of viable, calbindin-positive PCs decreased significantly at 24 h and 7 days after injury, and the percentage of surviving, aldolase C-positive PCs significantly increased at those time-points. In addition, we subjected murine cerebellar cultures to AMPA (30 microm, 20 min), which killed a significant number of PCs at 24 h post-treatment. A similar number of PCs was lost after transfection with aldolase C siRNA, and this effect was exacerbated in transfected cultures treated with AMPA. The results from the present study indicate that aldolase C provides marked neuroprotection to PCs after trauma and excitotoxicity.