Mechanisms of Seizure-Induced Death of TSC Model Mice
Abstract
This proposal addresses Tuberous Sclerosis Complex Research Program’s Focus Area Preventing epilepsy, improving treatment, and mitigating neurodevelopmental outcomes associated with TSC-related seizures. Compared to healthy control patients, those with Tuberous Sclerosis Complex (TSC) have an up to fivefold higher incidence of death. This is due to a number of factors, but the most substantial is sudden unexpected death in epilepsy (SUDEP). According to a recent analysis of the Tuberous Sclerosis Alliance Natural History Database, SUDEP is the most common cause of death for TSC patients. SUDEP is defined as the sudden, unexpected, nontraumatic, and nondrowning death of a person with epilepsy for which postmortem examination does not reveal another cause of death. As implied in this definition, how SUDEP occurs is not presently understood. Transgenic mouse models of TSC also experience high mortality rate; however, no research has been performed on the mechanism(s) of death in these mouse models (i.e., How do these seizures produce death?). Although a number of mechanisms have been proposed for SUDEP, they all culminate with eventual failure of breathing and/or heart function. My research program is focused on understanding how the brain controls breathing and cardiovascular function in health and disease. I have expertise in recording breathing and heart function and have already published results concerning SUDEP in other models of epilepsy, where I uncovered that respiratory arrest is the primary driver of fatality. Based on previous reports monitoring seizures in TSC mouse models, and my previous data in other SUDEP models, I hypothesize that seizures produce respiratory arrest, and fatality occurs when breathing does not recover immediately after the seizure. In Aim 1, I will record breathing and heart function in addition to seizure monitoring in two commonly used mouse models of TSC. The primary goals of this aim are to determine whether seizures initiate death and whether breathing or heart function fail to produce death. In Aim 2, I will record multiple lower brain regions that are important for control of breathing in addition to recording breathing and heart function. I will also administer the drug vigabatrin in one group of mice, which has been shown to nearly eliminate seizures, but modestly effect fatality in TSC mice. The goals of these experiments are to understand how mice die when vigabatrin is administered (e.g., as in Aim 1: from seizures; heart or breathing dysfunction), and to see what lower brain regions are activated during seizures and fatality. Although the experiments proposed are technically challenging and will have great impact for the field, they are straightforward and feasible. My approach allows for detailed recording of numerous mice 24 hours a day, 7 days a week. This ensures the success of my proposed experiments. When fatality occurs, I will be able to assess what happens to breathing and heart function: what fails first and how this relates to seizures. Results from these studies will be entirely novel, as work of this nature has never been attempted in TSC mouse models. It will provide future directions for understanding and preventing SUDEP in TSC mouse models. Ultimately, identifying the cause of death and neural mechanisms will produce therapies that prevent aspects of severe seizures and death in TSC patients. This would affect a large fraction of TSC patients and their families, as many with TSC have intractable convulsive seizures, putting them at high risk for SUDEP.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310378
Entities
People
- Ian Wenker
Organizations
- United States Army
- University of Virginia