Microcircuits of the Subiculum and Epilepsy

Seizures remain uncontrolled by medical therapy in roughly 30% of the patients suffering from temporal lobe epilepsy. Thus, the identification of neuronal mechanisms in microcircuits contributing to epileptogenesis and understanding the initiation, propagation and termination of seizures at the network level are key points for the development of novel/original therapeutic strategies. As such, they were explicitly included in the NINDS 2007 and 2014 Benchmarks for Epilepsy Research. The broad purpose of this application is to study the microcircuits of the subiculum, which is a region of the hippocampal formation critically involved in the generation and spreading of epileptiform activity. Although frequently overlooked, the subiculum serves as both the last integrative node and main output station of the hippocampal formation, and projects extensively both to cortical and subcortical areas. In addition to participating in several important physiological functions, such as spatial information processing, memory, motivation and the temporal control of behavior, the subiculum has recently emerged as a primary network involved in human temporal lobe epilepsy. In fact, the subiculum has been identified as the region most often initiating interictal activity, and its intrinsic microcircuits have been suggested to generate the preictal activity associated with interictal-ictal transitions. Because of its extensive extra-hippocampal projections, pathological activity in the subiculum is the culprit for spreading hippocampal hyper-excitability to other target regions, a necessary requirement for generalized convulsions. Currently, the surprising lack of knowledge of the functional organization of subicular microcircuits prevents a mechanistic knowledge of how local epileptiform activity is generated, spreads to other brain regions, or can be potentially controlled, all of which have been longstanding points of critical importance for progress. In particular, we will take advantage of state-of-the-art techniques (optogenetics, double and triple simultaneous patch clamp-recordings from connected neurons and post hoc anatomical identification in slices prepared from wild type and epileptic animals) to study the specific synaptic connectivity and excitability of subicular pyramidal cells and GABAergic interneurons, and relate these high-resolution findings to a newly discovered spontaneous synchronized subicular population activity that we have observed in vitro and that resembles highly synchronized network states in vivo.