Abstracts

Rationale: Epilepsy, a group of conditions characterized by sporadic occurrence of seizures and unconsciousness, is estimated to affect over two million people in the United States alone. Despite optimal current antiepileptic drug (AED) treatment, approximately 30% of patients have medically-intractable epilepsy. Most current AEDs affect neuronal channels and are accompanied with adverse effects including depression of cognition and memory. Since excitotoxic neuronal degeneration and gliosis are hallmarks of epilepsy, new drugs based on glial cell-specific targets of glutamate metabolism could provide an alternative approach with potentially fewer deleterious effects. Glutamate transporter-1 (GLT1) is an astrocyte-specific protein that is responsible for the majority of glutamate clearance from the synapse. However, the regulation of GLT1 in epilepsy models is not well characterized. Methods: In this study, we used the well-established intrahippocampal kainic acid (IHKA) model of epilepsy. Injection of kainic acid into the hippocampus of adult mice induces convulsive status epilepticus (SE) that subsides spontaneously. After a one-week latent period, mice experience chronic recurrent seizures and morphological changes in the hippocampus that resemble mesial temporal sclerosis. To determine expression changes of GLT1 during the development of epilepsy in this model, real-time polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analysis was performed at 1, 4, 7, and 30 days post SE. At each time point, n=5 mice were used for each analysis. Results: We found an initial increase in hippocampal GLT1 expression as early as one day post status epilepticus (SE) in the adult mouse brain. This significant increase subsided by 4 days post SE and was then followed by a significant and persistent downregulation of GLT1. Conclusions: These experiments demonstrated dramatic and significant GLT1 regulation following KA-induced status epilepticus (SE). Based on these results, GLT1 may represent a novel glial-specific therapeutic target for epilepsy. Future studies will identify the functional relevance of GLT1 regulation to epileptogenesis. This project was supported by NIH RO1s NS082540 and NS081243.