Genetic targets of epileptogensis and pharmacoresistance in brain glial cells

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Temporal lobe epilepsy (TLE) is a common serious chronic neurological condition. Due to frequent pharmacoresistance many patients have to undergo invasive removal of the hippocampus as the only alternative to achieve seizure control. Hence there is an urgent need to develop novel pharmacological treatment strategies.Several recent lines of evidence are pointing towards an important role of genetics in TLE. However TLE is characterized by a complex genetic architecture and probably consists of several different subgroups. To identify these subgroups and tailor pharmacological treatment to the respective is a major future goal and will benefit patients with this disabling condition. During the past decade, most genetic studies focused on polymorphisms in neuronal synaptic ion channel genes, and proved rather unsuccessful. Recent findings however suggest that modified glial function may play an important role in the hyperexcitability of neuronal tissue. Especially astrocytes are supposed to promote epileptogenesis and disease progression in epilepsy, and specifically in TLE. Astrocytes have important homeostatic functions in brain water- and ion homeostasis, mediated by specific water and potassium channels, AQP4 and Kir4.1, but are also critically involved in uptake of neurotransmitters via specific transporters, receptor-mediated Ca2+ signaling and gliotransmitter release.This project tests the hypothesis that astrocytes (more specifically astrocyte channels, receptors and intracellular pathways) play a critical role in generation, spreading, and maintenance of seizures in different TLE subgroups including TLE with hippocampal sclerosis (TLE-HS) and TLE after febrile seizures (TLE-FS). To do this we aim to focus on genetic studies on glia targets, functional studies in living human epileptic tissue and MTLE-HS mouse models, studies on knockout animals, and other functional and molecular biological studies. Investigation of glial function and genetic targets in glia cells, as it will be established in this collaboration, is a new and emerging field that may have direct clinical consequences for patients with pharmacoresistant TLE.