Ectopic kainate receptors in temporal lobe epilepsy: a new therapeutic target – TARGET-KAREP

Mesial temporal lobe epilepsy (TLE), one of the most common forms of epilepsy in adults, is frequently intractable. We have recently explored the pathophysiological implications of kainate receptors (KARs) in chronic seizures in a mouse model of TLE. We have demonstrated that aberrantly expressed synaptic KARs in the dentate gyrus of the hippocampus play a major role in chronic seizures in TLE and thus constitute a promising antiepileptic target. We now aim to extend our pre-clinic study from mice to human epileptic tissue. We propose to use slices from surgically resected hippocampus of intractable TLE patients to delineate the role of KARs in seizure activities in human tissues. The goal of the project is then to propose two parallel strategies to target aberrant synaptic KARs. The core of the project deals with the design and validation of cell-directed viral gene delivery vectors to silence KAR expression specifically in dentate granule cells. In parallel, we propose to induce destabilization of synaptic KARs recruited to aberrant recurrent mossy fiber-dentate granule cell synapses by preventing the interaction of KARs with transsynaptic proteins involved in the stabilization and recruitment of KARs at synapses. Importantly, the tools and strategies will first be tested in cellular systems and in animal models of TLE, and then comprehensively validated in human hippocampal tissues obtained from surgically resected patients with intractable TLE. Thereby, we will extend pre-clinic studies in animal models to pathophysiologically most relevant human epileptic tissue, which should pave the way for future clinical translation.