Abstracts

RATIONALE: Seizures follow excessive excitation associated with glutamate or from inadequate inhibition by -aminobutyric acid (GABA). Transporter proteins that remove amino acids from the synaptic cleft terminate synaptic effects. Glial transporters GLAST and GLT-1, and neuronal transporter EAAC-1, limit excitation initiated by glutamate. Transporter proteins GAT-1 and GAT-3 remove GABA from synaptic regions. METHODS: To assess the molecular effects of valproic acid, albino rats with chronic, spontaneous seizures induced by amygdalar FeCl3 were treated for 14 days with either valproic acid or with saline as control. Regions of the hippocampus were assayed for glutamate and GABA transporters by western blot. RESULTS: Valproate caused an increase in the quantity of GLAST protein in the hippocampus, and decrease in GLT-1 in both control and experimental animals. GABA transporters GAT-1 and GAT-3 in the hippocampus were up regulated by FeCl3 injection into the amygdala. Valproate caused down-regulation of these GABA transporters in both control and experimental animals. CONCLUSIONS: Altered molecular regulation of glutamate appears to be critical in the development of sustained, spontaneous limbic seizures. Our data suggest that valproate has unique mechanisms of action; specifically, it affects the removal of glutamate by up-regulating GLAST, and decreases GABA transport, resulting in increased tissue concentrations of GABA.