Lesion extent and seizure propagation pathways across acute infection and chronic epilepsy in an infection induced mouse model

University Of Iowa, Iowa City IA

Investigators

Abstract

Project Summary One in twenty-six individuals will develop epilepsy during their lifetime. A major cause of epilepsy worldwide is viral encephalitis. Infected patients are 16x more likely to develop epilepsy than the general population. Active infection can provoke seizures in the short term, but also increase the risk of spontaneous, recurrent seizures post-viral clearance. However, the mechanisms underlying seizures during the acute phase and the development of chronic epilepsy in the post-viral phase are unknown. The Wilcox lab and collaborators have developed the only mouse model of viral-induced temporal lobe epilepsy (TLE). C57Bl/6 mice injected with Theiler’s murine encephalomyelitis (TMEV) recapitulate features of human viral encephalitis: mice exhibit seizures 3-8 days post- infection (DPI), clear the virus by 14 DPI, and can eventually develop chronic TLE. TMEV infection induces inflammation, reactive gliosis, and cell death in the hippocampal CA1, which may contribute to acute seizure development. However, over half of previously infected animals will develop recurrent, spontaneous seizures long after viral clearance. This suggests differing etiologies between acute and chronically occurring seizures in TMEV. CA3 neurons are spared by TMEV infection and the amplitude distribution of CA3 mEPSCs varies across the acute and chronic phase. It is possible that hippocampal damage and consequential inflammation incite acute seizures, while long-term changes in hippocampal circuitry underlie the chronic seizures. The progression of TMEV-induced hippocampal lesions and underpinnings of acute vs chronic seizures are gaps in our knowledge that this proposal aims to address. We will quantify TMEV-induced cell loss and use targeted recombination in active populations (TRAP) to map the epileptogenic zone and seizure propagation networks during discrete post-infection timepoints. In Aim 1, we will perform immunolabeling-enabled 3-dimensional imaging of solvent cleared organs (iDISCO) in TMEV-infected mice at 5 DPI (seizure peak), 14 DPI (after acute seizures resolve and the virus is cleared), and following the first recorded chronic, spontaneous seizure to determine the extent and progression of lesions in the acute and chronic phase of TMEV infection. In Aim 2, we will determine seizure propagation pathways in TMEV-infected mice following seizures in the acute vs chronic phase by tagging neurons active during seizures at 5 and 14 DPI and the chronic phase with TRAP. Activated circuitry will then be quantified to compare seizures across the course of TMEV infection and the subsequent development of TLE. Participation in the proposed training plan and completion of these experiments will advance my neuroscience training in pursuit of a career as an independent epilepsy researcher. It will also address crucial questions about epileptogenesis across TMEV infection. These experiments are the foundation for a future K99 aimed at manipulating the regions, networks, and cell types identified here. It is our hope that we may discover critical clues to novel treatments for epilepsy patients.