Neural circuit mechanisms controlling seizures

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Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is associated with significant cognitive decline. In over 40% 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 timescale of seconds to minutes. Using 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, preliminary results identified a distinct cluster of cells within the hippocampus prominently active during seizures. Additional preliminary work identifies this region as also involved during interictal epileptiform events, suggesting it is a critical control node in the development of seizures. This proposal will employ two different models of TLE, a recently developed focal genetic knockout model and the intrahippocampal kainite model, to dissect the role of this ensemble and 1) Determine its involvement in both interictal and ictal activity in chronically epileptic animals; 2) Determine whether optogenetic inhibition of these cells during seizures can control chronic spontaneous seizures and its associated cognitive comorbidities 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 has assembled an Advisory Committee comprised of Gyorgy Buzsaki, Liqun Luo, and Alice Ting to support the acquisition of additional training in closed-loop control of neuronal oscillations, cleared tissue imaging and gene expression analysis, and molecular tool development. In addition, the candidate proposes a personalized plan for career development comprised of additional experience in grant writing, teaching, and scientific management to facilitate 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 1) Establishing a previously unknown relationship between interictal and ictal activity; 2) Identifying the therapeutic potential of intervention in a previously unexplored area of the hippocampus to control seizures and associated cognitive deficits; and 3) Identify seizure-specific cellular ensembles for further study. The training period afforded by the K99/R00 award will allow the candidate to develop a powerful set of skills and resources to use in her independent career and the interdisciplinary nature at Stanford provides the ideal environment for the candidate to carry out the research and training plan successfully.