IntActE

Characterizing Interaction between Target Regions for Activity Propagation in Epilepsy

Summary

Although epilepsy is often called a ‘network disease’ the research mostly focuses on alterations in one brain area without analyzing its effect on downstream targets in the network. Understanding these interactions in detail, however, might contribute to a better understanding of how epileptic activity spreads in the brain and ultimately to data-driven instead of explorative approaches where to interrupt the propagation for successful seizure intervention. During the last years we have characterized the hippocampal CA2 region as a downstream target of the well-investigated dentate gyrus in a mouse model for temporal lobe epilepsy (TLE) and in tissue from resective epilepsy surgery in patients. We found that the synaptic integration of CA2 region into the hippocampal network is altered in a pro-epileptogenic fashion (Häussler et al., 2016, Hippocampus), that it strongly contributes to epileptic activity (Tulke et al., 2019, Epilepsia; Kilias et al., in prep) and that projections to downstream targets are at least in parts preserved. One important downstream region that receives axonal projections from CA2 is the subiculum which due to its widespread connectivity offers a pathway for activity propagation to various cortical and subcortical targets. Within the current proposal we aim to investigate the interaction of the CA2 region and the subiculum by combining electrophysiological in vivo recordings in the subiculum with chemogenetic (applying designer receptors exclusively activated by designer drugs (DREADDs)) inhibition or excitation of the input from CA2. This approach requires high quality multi-unit, multi-site recordings with long-term stability and minimal tissue damage to guarantee best preservation of the connectivity between the two regions to being able to find also small variations induced by the manipulation. To this end we will closely interact with the project proposed as ‘StiffFlex’ which will provide us with different types of soft and stiff neural probes to determine which approach offers the best methodology to fulfill the biological requirements. In return, we will offer an in vivo application in freely moving mice to provide electrophysiological data resulting from the various approaches to complete the studies on probe tissue interaction as proposed in the project.