Controlling epilepsy symptoms with precisely timed inhibition and circuit editing

About This Grant

PROJECT SUMMARY/ABSTRACT Temporal lobe epilepsy (TLE) is a complex neurological disorder that is characterized by spontaneous, reoccurring seizures and often presents with debilitating cognitive comorbidities including learning and memory deficits. Current treatments for TLE are ineffective at managing cognitive comorbidities and often exacerbate these symptoms. The mechanisms underlying cognitive impairments in TLE are poorly understood, but learning and memory deficits are thought to arise when TLE pathologies disrupt the normal function of hippocampal circuits that support these cognitive processes. Circuits in the hippocampal dentate gyrus (DG) are known to support learning and memory and have been shown to be disrupted in TLE patients and in animal models of TLE. Recently, Dr. Shuman showed that the spike timing of DG interneurons is disrupted in TLE. Additionally, he showed that restoring proper spike timing of DG interneurons with closed-loop optogenetic stimulation decreased seizure susceptibility in TLE mice. Because proper spike timing in the hippocampus is an important mechanism that supports learning and memory computations, I hypothesize that DG interneuron spike timing is also important for behavior. In aim 1, I will test this hypothesis by using closed- loop optogenetic stimulation to alter the spike timing of DG interneurons relative to ongoing theta oscillations. I predict that disrupting DG interneuron spike timing in non-epileptic mice will impair learning and memory while restoring the disrupted spike timing of DG interneurons in TLE mice will restore learning and memory deficits. While optogenetic approaches are great for assessing the causal relationships between physiological processes and behavior, there are a number of barriers that limit the translational potential of optogenetics. In aim 2, I will employ a novel circuit-editing tool to increase connectivity between DG interneurons and their upstream inputs in the medial entorhinal cortex (MEC) with the goal of increasing feedforward inhibition in the DG. I hypothesize that increasing connectivity to DG interneurons will decrease seizure susceptibility. Additionally, I predict that this approach will restore the proper spike timing of DG interneurons because inputs fire at the same preferred phase of theta as DG interneurons and are not disrupted in TLE. Circuit-editing is a novel technique that has never been applied to epilepsy. Successful implementation of this approach could result in a transformative gene therapy for epilepsy patients and will inform how feedforward inhibition in the DG normally supports hippocampal physiology. The following research project and training plan were designed to help me grow both scientifically and professionally, and support from this grant will be invaluable as I continue to work towards my goal of becoming an independent researcher. The outstanding opportunities provided by the Shuman lab and Mount Sinai provide the ideal training environment for me as I pursue my postdoctoral fellowship and ultimately a career in academic research.