Abstract 2033 Poster Session II, Sunday, 5/2 (poster 228)

Hypoxia-ischemia (HI) in newborns produces cerebral injury with potentially devastating long-term neurobehavioral consequences. In a model of global HI in newborn piglets there is a characteristic regional and temporal sequence of neurodegeneration. The basal ganglia show selective vulnerability that rapidly progresses in the first 24 hours after HI. A HI-induced increase of extracellular glutamate in the striatum may contribute to the excitotoxic cell injury. A family of glutamate transporters (GLT1, GLAST, and EAAC1) maintains physiological, non-excitotoxic extracellular glutamate concentrations. We hypothesized that defective glutamate transport in the striatum occurs early during recovery after HI in newborn piglets. One-week-old piglets were subjected to 30 minutes of hypoxia (arterial O2 saturation 30%), followed by 7 minutes of airway occlusion (arterial O2 saturation 5%), resulting in asphyxic cardiac arrest. Recovery for 3, 6, 12 or 24 hours followed cardiopulmonary resuscitation and return of spontaneous circulation. The corresponding percent of neurons with ischemic cytopathology in the putamen was 16%, 31%, 47%, and 79%. Synaptosomes were prepared from freshly frozen striatal samples. High-affinity [3H]-glutamate transport was 100%, 64%, and 52% of control levels at 3, 6/12, and 24 hours of recovery. HI did not alter either the affinity constant (Km) nor the number of transporter sites (Vmax) compared to control values. Therefore, defects in high-affinity glutamate uptake occur early and coincide with ongoing neurodegeneration in the striatum. Previous studies of type-specific glutamate transporter expression in newborn piglet striatum following HI have shown decreases in GLT1 and EAAC1 proteins, with no alteration in GLAST expression. We conclude that reduced high-affinity glutamate transporter function along with decreased GLT1 and EAAC1 expression may combine to create inadequate extracellular uptake, and thus provide a mechanism for early striatal excitotoxic neurodegeneration following HI in newborn piglets.

Funded by the American Academy of Pediatrics New Investigator Grant, NS 20020 and NS 34100.