Neural circuit mechanisms controlling seizures

Vanderbilt University, Nashville TN

Investigators

Linked publications, trials & patents

Abstract

Project Summary/Abstract Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is associated with significant cognitive decline. In over 30% of TLE cases, seizures are not controlled with current treatment options and systemic anti-epileptic drug administration can have major negative side effects, prompting the need for more effective therapies. However, the cellular and circuit mechanisms underlying TLE are not yet understood due to the inherent challenges of studying chronic spontaneous seizures which typically occur within a relatively short temporal window, often on a time-scale of seconds to minutes. During the K99 phase the candidate was able to use a recently developed molecular tool, which integrates light and calcium to label active cells within a short temporal window, along with a closed-loop system for seizure detection and light delivery, to identify a distinct cluster of cells within the hippocampus prominently active during seizures. Additional work identified this region as also involved during interictal epileptiform events, suggesting it is a critical control node in the development of seizures. This proposal for the R00 phase will employ two different models of TLE, a recently developed focal genetic knockout model and the intrahippocampal kainate model, to dissect the role of this cellular ensemble and 1) Determine changes in the excitability of these cells in epilepsy; 2) Determine whether optogenetic inhibition of these cells during seizures can control cognitive comorbidities of epilepsy using a transgenic mouse line that provides access to this distinct population of cells; and 3) Determine whether early intervention in this region can prevent the progression of epilepsy and its associated cognitive comorbidities. The candidate will be transitioning to a tenure-track Assistant Professor faculty position at Vanderbilt University which is committed to supporting the candidate’s research and career goals and facilitating their success as an independent researcher. The candidate’s long-term goal is to develop a career as an independent neuroscientist utilizing multi-scale investigation at the level of molecules, cells, circuits, and behavior to understand mechanisms of neuronal function and their dysfunction in neurological disorders such as epilepsy. Completion of the proposed study will advance the field by identifying mechanisms that lead to hyperexcitability in the brain and identifying the therapeutic potential of intervention in a previously unexplored area of the hippocampus to control seizures and associated cognitive deficits. The support afforded by the R00 award will allow the candidate to cultivate her independent career and the interdisciplinary nature at Vanderbilt provides the ideal environment for the candidate to carry out the research and career development plan successfully. The administrative supplement will aid the candidate’s return to full research productivity after maternity leave by providing funds to bridge support for existing personnel.