Abstracts

Rationale: Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adulthood and also the most common form of drug-resistant epilepsy. Several studies implicate high extracellular glutamate levels in the hippocampus of patients with TLE as a contributing factor for the development of epilepsy. Microdialysis studies have demonstrated that patients with drug-resistant TLE present higher inter-ictal extracellular glutamate levels within the hippocampus, and that further increases occur during seizures. Glutamate released from neurons is normally taken-up by astrocytes via glutamate transporters and subsequently converted to glutamine by the enzyme glutamine synthetase (GS). Here we hypothesized that the glutamate levels will also be increased in the necortex from drug-resistant TLE patients and this will be associated with reactive astrogliosis and decreased astrocytic GS expression.Methods: A total of 10 subjects with confirmed drug-resistant TLE ages 20-56 years (mean 35.7) were prospectively enrolled in this study. Neocortical samples were collected following brain surgery for drug-resistant epilepsy at the Hospital of the University of Pennsylvania. Patients with temporal lobe lesions other than mesial temporal sclerosis (MTS) were specifically excluded. Control tissue was obtained from the NICHD Maryland Brain and Tissue Bank and was matched for age (n=5). The study was approved by the University of Pennsylvania IRB and all patients were consented prior to tissue collection. The expression of glutamate and GS were assessed by Western blot and immunohistochemistry.Results: The evaluation of cortical samples from TLE patient showed significantly higher glutamate levels (464.8 ± 134.3% of control, n=10 P=0.04) and lower GS levels (80.51± 5.8% of control, n=9, P=0.036) in the lateral temporal cortex. Immunohistochemical analysis demonstrated an overall increased glutamate expression in neuronal cell bodies, axons and astrocytic processes. GS was decreased in reactive astrocytes throughout the cortex, but showed a striking upregulation in the astrocytic processes surrounding the blood vessels.Conclusions: These results demonstrate a broad dysregulation of the glutamate metabolism associated with astrogliosis in patients with drug-resistant TLE. Further investigation of this system, in particular elucidating the mechanisms responsible for GS deficiency in these patients, could be relevant to development of new therapies for refractory TLE.