gms | German Medical Science

Objective: Epilepsy is one of the most common neurological disorders with a lifetime incidence of 3%. While many patients can be sufficiently treated with anticonvulsant drugs, about one third remains pharmacoresistent. Over the past years the development of novel drugs resulted in an increase of treatment options. Nevertheless, none of the new compounds allowed a successful treatment of the majority of intractable cases. At the same time the mechanism underlying drug resistance are largely not understood. In this ongoing project we established a model system based on human tissue from resective epilepsy surgery to study mechanisms of drug resistance.

Method: Approval of the ethics committee of the University of Tübingen as well as written informed consent was obtained from patients, allowing spare tissue to be included in our study. Cortex was carefully microdissected and resected with only minimal use of bipolar forceps to ensure tissue integrity, transferred into icecold aCSF equilibrated with carbogene (95%O₂, 5%CO₂) and immediately transported to the laboratory. Tissue was kept submerged in cool and carbogeneated aCSF at all times. After removal of the pia tissue chunks were trimmed perpendicular to the cortical surface and thick acute slices were prepared using a vibrating microtome.

Results: State-of-the-art whole cell patch clamp recordings of human cortical neurons in combination with morphological reconstruction after biocytin filling and extracellular field recordings were performed and demonstrated viability of microsurgically resected cortical tissue. Application of the M-current activator ICA-27243 modulated network and single neuron activity, confirming tissue integrity and feasibility of our experimental approach.

Conclusions: This model system in combination with other studies, including investigation of drug transporters in the blood-brain-barrier, will serve as a platform to study mechanisms of drug resistance in patients suffering from intractable epilepsy.