Kainate receptors in acute and chronic mouse models of epilepsy – KAREP

The present project explores the pathophysiological implication of a family of ionotropic glutamate receptors, kainate receptors (KARs) in acute and chronic models of temporal lobe epilepsy (TLE). This project takes advantage of the use of KAR-subunit deficient mice and selected pharmacological agents, and will be based on the expertise of the partners in electrophysiology techniques, both in slices and in vivo. The general question we want to address is the implication of the physiological activation of KARs by its endogenous agonist glutamate in epileptogenesis and excitotoxicity through the analysis of KAR-subunit deficient mice in acute and chronic models of temporal lobe epilepsy. The aim is to provide a rationale for the test and discovery of new antiepileptic drugs and to promote new therapeutic strategies. Finally, this project involves the development for the first time in France of a unique set-up for intracellular recordings in awake mice performing spatial behaviour in a virtual reality environment. This will allow investigating the mechanisms of altered coding in the chronic epileptic brain with unprecedented details.
The project brings together two internationally-recognized French groups with a complementarity in expertise, and with a common general aim to better understand the role of kainate receptors in the pathophysiology of the brain. Whereas the group of Christophe Mulle has developed molecular and genetic tools to study the role of kainate receptors in the brain, using cell biology and synaptic physiology, the group of Valérie Crépel has a long standing interest in the mechanisms of epilepsy. This project takes advantage of newly developed mutant mouse models which are adapted to the study of mouse TLE models, and which are not available elsewhere.
This project is divided into the 5 following tasks:
• Analyse the susceptibility of KAR-subunit deficient mice (GluR5, GluR6 GluR7 and KA2) to epileptic seizures and hippocampal neurodegeneration in acute models of temporal lobe epilepsy: KA, pilocarpine and PTZ.
• Test the antiepileptic activity of selected KAR antagonists in wild-type and KAR-subunit deficient mice.
• Analyze the role of KARs in synaptic remodelling in the DG in a chronic model of TLE, and in the possible overexcitation mediated by recurrent collaterals.
• Provide a proof of concept that KAR interacting peptides injected in vivo can regulate KAR-EPSCs at recurrent mossy fiber EPSCs and epileptiform activity in a chronic model of TLE.
• Determine the role of aberrant KAR-operated synapses in temporal coding alterations in chronic epileptic rats and how KARs antagonists could improve the behavioural outcome in chronic epilepsy.
Overall, the KAREP project constitutes the first comprehensive study on the role of KAR subtypes in acute and chronic models of epilepsy. In addition, it will provide new possibilities for targeting synaptic KAR-EPSCs that potentially play a fundamental role in the occurrence of recurrent epileptic activity in a chronic model of TLE.