In Europe, 3.4 million people suffer from epilepsy and 310.000 new cases are diagnosed each year. A large number of patients suffer from uncontrolled seizures or severe medication-related side effects. Thus there is a pressing need to develop new therapies that successfully control seizures without side effects. Chemogenetics is a type of gene therapy where cells are induced to express a mutant receptor that is not activated by endogenous ligands but can be activated by specific drugs at dosages that otherwise have no effect. This technology can be used to selectively inhibit specific cell types in specific brain structures. In this project we will use this technology to suppress the activity of excitatory neurons inside the seizure focus (hippocampus) of rodent models for temporal lobe epilepsy (TLE) to suppress spontaneous epileptic seizures. In a mice model for drug resistant TLE this approach showed to be very potent. In a next step we will target chronic seizure suppression in a rat model for TLE and evaluate the effect on epilepsy co-morbidities. Additionally we will improve the designer receptor to make it less vulnerable for regulatory processes thus improving its potency to chronically suppress seizures. In theory this would be an ideal treatment with high therapeutic potential and low risk for side effects since it allows focal treatment of a seizure focus with peripheral administration of a drug at subtreshold dosages.