Authors :
Presenting Author: Alexandra Petrucci, PhD – University of Iowa
Ted Abel, PhD – University of Iowa
Karen Wilcox, PhD – University of Utah
Rationale:
Epilepsy affects over 65 million individuals worldwide. A major cause of epilepsy is viral encephalitis. Central nervous system infections can provoke seizures in the short term and increase the risk of acquired epilepsy post-infection. However, the neural mechanisms underlying seizures during acute infection are unknown.
Methods:
TMEV-infected mice recapitulate many features of viral encephalitis in patients. The mice experience seizures 3-8 days post-injection (DPI), clear the virus by DPI 14, and may develop chronic, acquired temporal lobe epilepsy. TMEV may incite seizures during the acute infection period through inflammation, reactive gliosis, and cell death in the hippocampus. Here, we explore the neuronal circuits underlying acute seizures in TMEV-injected mice using c-Fos driven targeted recombination in active populations (TRAP) mice. TRAP mice (c-Fos-CreERT2 x CAG-tdTomato) were injected with PBS or TMEV and gently handled on DPI 5 to induce seizures. 4-OHT was administered to mice at one of two timepoints (1.5 or 3 hr) after seizures to tag the active cells expressing c-Fos with tdTomato. After 1 week, the mice were sacrificed and whole mouse brains were sectioned and immunostained for tdTomato expression.
Results:
Percent area of fluorescence was quantified, and comparisons were made between TMEV-injected mice and PBS controls, sites ipsilateral vs contralateral to TMEV injection site, and between sexes. TdTomato expression was elevated in the TMEV-injected mice in the ipsilateral and contralateral hippocampus, thalamus, lateral septal nucleus, basal ganglia, triangular septal nucleus, fornix, and corpus callosum. Critically, the expression pattern of tdTomato suggests that seizures induced on DPI 5 likely arise from the hilus, dentate gyrus, and CA3 hippocampal subregions. Consistent with the observed generalized seizures, tdTomato expression was robust in the ipsilateral and contralateral hemispheres. Likewise, TRAP mice administered 4-OHT at both the 1.5 or 3 hr exhibited greater tdTomato expression than controls, but tdTomato expression was lower in the white matter structures of mice injected at 3 hr.Conclusions:
Generalized seizures during acute TMEV infection may have propagated to the contralateral hemisphere via CA3 and the hippocampal commissure. TRAP has not been previously utilized in the TMEV mouse model and these experiments address crucial questions regarding seizure spread during TMEV infection. Funding:
This work was supported by the Iowa Neuroscience Institute Post-doctoral Fund and National Institutes of Health/National Institute of Neurological Disease and Stroke 1T32NS115723-01 and 1F32NS136186 to A.N.P. The National Institutes of Health/National Institute of Neurological Disease and Stroke Javits Award R37NS065434 and the NINDS Landis Award for Outstanding Mentorship (2022) to K.S.W. T.A. is supported by the Roy J. Carver Chair of Neuroscience and R01 MH087463.