Astroglial Glutamate Transporter GLT-1 is Reduced in Parietal Neocortex Following Hypoxia-Ischemia in Newborn Piglets: A Possible Molecular Mechanism for Subsequent Seizures and Neocortical Neurodegeneration • 1879

Abstract

Perinatal hypoxia-ischemia (HI) is a risk factor for neurological disabilities such as cerebral palsy and seizures and threatens the life and future development of newborn infants. The excitatory amino acid glutamate plays an important role in the pathophysiology of HI brain damage. Uptake of extracellular glutamate by transporter proteins such as the astroglial GLT-1 is essential to avoid excessive accumulation of synaptic glutamate which can cause seizures and excitotoxic neuronal death. In a newborn piglet model of HI that causes damage to the basal ganglia and delayed seizures, we tested the hypothesis that defects in glutamate transporters occur in the neocortex at a time prior to the evolution of neocortical neuropathology. Newborn piglets(≈1 week old, n=7) were subjected to 30 minutes of hypoxia (FiO2 10%) followed by 7 minutes of airway occlusion resulting in cardiac arrest requiring resuscitation. At 24 hours recovery, we evaluated neurological deficits, the levels of GLT-1 protein in the parietal and occipital cortex as well as neuronal damage in the parietal cortex (layers II/III) and the striatum. The mean neurological deficit score was 22 on a scale of 0 (normal) to 150 (comatose). By immunoblotting, GLT-1 levels in the parietal cortex(expressed as the ratio of GLT-1 and β-tubulin to correct for protein loading) were 70% of control (n=4 control piglets). GLT-1 expression in parietal cortex was 32% of occipital cortex levels in HI piglets. Neuronal injury at 24 hours recovery in the parietal cortex layers II/III was minimal(mean = 1.3% neuronal damage); however, all piglets received an effective ischemic insult because the striatum was damaged, consistent with previously established patterns. HI piglets with the greatest injury in the putamen at 24 hours had the lowest GLT-1 levels in the parietal cortex. We conclude that the loss of GLT-1 in parietal cortex correlates with the severity of degeneration in the striatum (a relationship that is possibly dictated by corticostriatal connectivity) and is a possible mechanism for the induction of delayed seizure activity and neocortical neurodegeneration following HI in newborns.