The research proposal is focused on deciphering the mechanisms causing febrile and afebrile seizures, especially in cases of genetically linked epileptic encephalopathies such as Dravet syndrome. A specific short- term goal is to understand how fever interacts with genetics to increase seizure susceptibility. In the long-term, I aim to incorporate genetic, circuit, and systems approaches to identify the causal mechanisms underlying autism and epilepsy. To achieve my goals, I have developed a 2-year training plan for learning advanced physiology techniques such as in vivo whole-cell recordings, two-photon calcium imaging and electroenceph- alogram recordings. These new skills will help expand my expertise into epilepsy research, and provide a strong platform to build my independent research program. This training plan is rich in career development activities that will provide essential avenues for me to optimize my skills in mentoring students, writing papers, and presenting scientific talks. In research during Phase I, I will build on my preliminary findings, which show that temperatures within the fever range can decrease parvalbumin-positive (PV) interneuron-mediated feedforward inhibition, a process I refer to as fever-induced depression of inhibition (FIDI).
My aims are therefore focused on establishing whether there is a causal link between FIDI and seizures in multiple mouse models of febrile seizures, and during the early postnatal stages of interneuron development. To complete the work during the mentored phase, I have assembled a panel of experts that includes my mentor Dr. Daniel Feldman, an expert in neurophysiology, and my scientific advisors Dr. Yang Dan, a leader in the field of cortical neurophysiology, Dr. Daniela Kaufer, an expert in epileptogenesis mechanisms, and finally Aristea Galanopoulou, a clinical board certified epileptologist and neurophysiologist. The combination of this excellent advisory team as well as the outstanding facilities provided by UC Berkeley will ensure that I make significant progress towards my research and career goals. This training plan lays the groundwork for research to be done during Phase II. The first research goal of Phase II is to establish causal roles for PV-mediated inhibition in promoting both febrile and afebrile seizures. Specifically, in a first aim I will test whether febrile and afebrile seizures can be blocked or delayed by chemo-genetically up-modulating local PV interneuron firing rates. I will also examine the cellular and synaptic mechanisms in PV interneurons that could underlie FIDI. In a second aim, I will use chronic two-photon calcium imaging to characterize the temporal dynamics of network activity changes within the pyramidal neurons and multiple interneuron cell populations during the period between febrile and spontaneous seizure onset.
This aim will identify the vulnerable timeframe when intervention may be successful in hindering the progression from febrile to afebrile seizures. As a whole, the work of Phase I and Phase II will delineate potential synaptic and cellular mechanisms underlying the onset of febrile and afebrile seizures and will prepare me for a successful transition to becoming an independent investigator.
It is clear that body temperature elevation acts as a precipitating factor for seizures associated with fever (febrile seizures), but the mechanisms underlying how elevated temperature promotes seizures are largely unknown. In most children, febrile seizures occur as isolated events, but in some children with a genetic predisposition, febrile seizures occur frequently and can rapidly progress to afebrile (spontaneous) seizures. The goal of my research is to show that fever depresses synaptic inhibition, which drives the onset of febrile seizures, and that additional alterations occur within select inhibitory circuits to then drive the onset of afebrile seizures.