Abstracts

RATIONALE: Epilepsy is a condition in which the brain is rendered electrically unstable due to a genetic abnormality or an underlying derangement, such as major head trauma, stroke, or benign and malignant gliomas. Approximately 75% of patients with central nervous system gliomas develop seizures. The hyperexcitable state of the epileptic brain results from a disruption in the balance between excitation and inhibition. Glutamate transporters involved in glutamate clearance out of the synatptic cleft have been implicated in the manifestation of seizures. Expression of the glutamate transporter EAAT2 is decreased in the brains of epileptic patients as well as in experimental models of epilepsy. Glutamate transporters function to maintain extracellular concentrations of glutamate below neurotoxic levels and prevent neurotoxicity. Neuronal cell loss accompanies and may contribute to glioma-related epileptogenesis. However, it remains controversial whether cell death precedes seizure activity or if cell death is a consequence of seizures. We hypothesize that increased glutamate transport will decrease glioma associated seizure activity and provide neuroprotection against neuronal cell death.
METHODS: Recently, our laboratory established a transgenic mouse model which overexpresses the glutamate transporter, EAAT2. Seizures were induced in wild type and EAAT2 overexpressing mice by injection of two million C6 glioma cells into the motor cortex. Epileptiform activity was assessed in vivo by electroencephalogram (EEG) recording and in vitro by extracellular recording in the hippocampal slice model. Cell death was analyzed over the course of tumor progression by TUNEL analysis and neuronal cell counts.
RESULTS: Using this model, we demonstrate that increased glutamate uptake attenuates glioma-associated epileptiform activity both in vivo and in vitro. In addition, the slow onset of seizure activity in the glioma model enables us to analyze cell death over the course of seizure induction. Here we demonstrate that cell death occurs in the cortex and bilaterally in the hippocampus prior to seizure onset and increased glutamate transport decreases the extent of neuronal cell loss.
CONCLUSIONS: These findings suggest a model for glioma-induced epileptogenesis in which cell death shifts the balance between excitation and inhibition, resulting in glutamatergic overexcitation. Glutamate transport may be a therapeutic target for the treatment of glioma-induced neurologic damage and secondary epileptogenesis.