Closed-loop Control of Interneuron Spike Timing in Epilepsy

Project Summary/Abstract – FROM PARENT GRANT Temporal lobe epilepsy (TLE) is a debilitating disorder that includes chronic seizures and pervasive memory impairments that significantly impact quality of life. In rodent models of TLE, my lab and others have found dramatic changes in brain synchronization with specific changes in the theta phase locking of individual interneurons of the dentate gyrus. However, it remains unclear whether this abnormal phase locking is a causal mediator of seizures and cognitive deficits in epilepsy. In order to test whether the timing of interneuron activity is directly controlling epileptic phenotypes, we have developed a novel closed-loop optogenetic system to control the timing of interneuron activity during behavior. In this proposal, we will use our closed-loop optogenetic system to shift the phase locking of parvalbumin- or somatostatin-expressing interneurons and determine how the timing of these interneurons alters seizure susceptibility and cognitive performance. In control mice, we will force an abnormal firing pattern onto the interneurons and determine whether this can drive increased seizure susceptibility and impair cognition. In epileptic mice, we will use optogenetics to normalize the timing of interneuron activity and determine whether this can reduce seizure susceptibility and rescue memory impairments. Together, these experiments will determine how the timing of interneuron activity mediates seizures and cognitive deficits in epilepsy.