Bioenergetics and Neuronal Network Remodeling in a Rodent Model of Temporal Lobe Epilepsy

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Epilepsy affects 3 million adults and 450,000 children in the US. One-third of chronic epilepsy is intractable to current antiseizure medications. Temporal lobe epilepsy (TLE), the most frequent form of acquired epilepsy, is typically initiated by brain injury, such as status epilepticus (SE), followed by a latent period wherein molecular and cellular remodeling occurs leading to chronic epilepsy. The process of remodeling is poorly understood. Not every patient who experiences episodic SE will progress to TLE, and the latent period of epileptogenesis can vary from weeks to years. There is a critical need for new mechanistic understanding and early recognition of post-SE TLE for risk stratification and better management. Mitochondrial dysfunction is increasingly recognized as an inciting factor for TLE, not only acutely after SE, but also contributing to epileptogenesis for refractory TLE. However, there are major knowledge gaps in disease thresholds and a lack of sensitive in vivo tools to detect and monitor the subclinical epileptogenesis process for early intervention before epilepsy is established. Our long-term goal is to understand the remodeling process that leads from SE to TLE. As an important step towards this, we are now in a strong position to test the HYPOTHESIS that a novel 4D oxy-wavelet MRI can be a proxy to detect foci with mitochondrial dysfunctions in post-SE injury that can contribute to TLE development. The focus of the current proposal is to validate and establish 4D oxy-wavelet MRI as a biomarker for identifying brain foci with mitochondrial dysfunctions. We will first validate 4D oxy-wavelet MRI as a non-invasive, region-specific means of monitoring mitochondrial function in the brain. We will use the well-known mitochondrial drugs, rotenone and 2,4-dinitrophenol, to pharmacologically impair or enhance mitochondrial respiration, respectively. Then we will monitor spatiotemporal evolution of region-specific changes in mitochondrial functions with 4D oxy-wavelet MRI in a post-SE TLE rat model. The 4D oxy-wavelet MRI signal will be correlated with ex vivo mitochondrial functional assays, including Oroboros respirometry, and brain metabolic profiling with in vivo MR spectroscopy. Our study will validate 4D oxy-wavelet MRI as a non-invasive method for monitoring mitochondrial activity in the brain. Using a rat model of post-SE TLE, we will use the new MRI tool to observe temporal and region- specific changes of mitochondrial function. These data can advance use of the 4D oxy-wavelet MRI as a non- invasive biomarker for predicting post-SE TLE. As this method is non-invasive, it can be translated to clinical setting in the future.