Cortico-hippocampal circuit dysfunction in an Scn1a mouse model of epilepsy

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PROJECT SUMMARY This mentored career development award proposal describes an integrated training program to prepare me to lead an independent R01-funded biomedical research laboratory focused on the study of epilepsy. Candidate: I am an Instructor and Research Fellow in the Department of Neurology at the Hospital of the University of Pennsylvania (Penn). I am a board-certified neurologist and a circuit neuroscientist with expertise in the technique of optogenetics, gained through my PhD in the laboratory of Dr. Karl Deisseroth. This proposal is designed to fill my gaps in expertise in experimental epileptology and in state-of-the-art large-scale imaging methods in brain slice and in vivo. My long-term goal is to use pre-clinical mouse models of epilepsy to motivate development of mechanistically oriented therapies to transform patient care. Environment: I will have dual-mentorship from Dr. Goldberg (primary mentor) and Dr. Jensen (co-mentor and senior career mentor), who have together successfully co-mentored my NIH NINDS R25 research fellowship. Dr. Goldberg is an Assistant Professor of Neurology and Neuroscience at the Children's Hospital of Philadelphia (CHOP). He is a rising star in the department who has provided me with invaluable hands-on training at the bench as well as mentorship from the perspective of a successful junior faculty member and physician-scientist. Dr. Jensen is Chair of the Department of Neurology. She is an outstanding physician-scientist in epilepsy with a passion for and well-established track record of mentorship. My mentors and I have constructed a mentorship team and career development plan to guide the execution of the proposed studies and my transition to independence. Training will occur at CHOP and at Penn, an academically enriching neuroscience community with extensive resources and opportunities for scientific interaction, including a wide range of available coursework and multiple ongoing seminar series in neuroscience, neurology, and epilepsy. This application is supported enthusiastically by the Department of Neurology at Penn. Research: My preliminary experiments in Dr. Goldberg’s laboratory have identified a profound hyperexcitability in the cortico-hippocampal circuit within a mouse model of genetic epilepsy (Scn1a+/-), suggesting a circuit-level convergence with mouse models of acquired temporal lobe epilepsy. The proposed research will identify the microcircuitry underlying this finding, and will test the hypothesis that this circuit is critical for the generation of seizures in the temporal lobe. These outcomes will provide novel insights into mechanisms of this important genetic epilepsy, as well as establishing more broadly a circuit-level pathogenesis underlying temporal lobe- onset seizures. This mentored career development award will position me to translate the insights gleaned from basic neuroscience research to inform and motivate future attempts at the targeted treatment of epilepsy.