Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy

Abstract

Central nervous system (CNS) infection can induce epilepsy that is often refractory to established antiseizure drugs. Previous studies in the Theiler’s murine encephalomyelitis virus (TMEV)-induced mouse model of limbic epilepsy have demonstrated the importance of inflammation, especially mediated by tumor necrosis factor-α (TNFα), in the development of acute seizures. TNFα modulates glutamate receptor trafficking via TNF receptor 1 (TNFR1) to cause increased excitatory synaptic transmission. Therefore, we hypothesized that an increase in TNFα signaling following TMEV infection might contribute to acute seizures. We found a significant increase in both mRNA and protein levels of TNFα and the protein expression ratio of TNF receptors (TNFR1:TNFR2) in the hippocampus, a brain region most likely involved in seizure initiation, following TMEV infection which suggests that TNFα signaling, predominantly through TNFR1, may contribute to limbic hyperexcitability. An increase in hippocampal cell surface glutamate receptor expression was also observed during acute seizures. While pharmacological inhibition of TNFR1-mediated signaling had no effect on acute seizures, several lines of genetically-modified animals deficient in either TNFα or TNFRs had robust changes in seizure incidence and severity following TMEV infection. TNFR2^-/- mice were highly susceptible to developing acute seizures, suggesting that TNFR2-mediated signaling may provide beneficial effects during the acute seizure period. Taken together the present results suggest that inflammation in the hippocampus, caused predominantly via TNFα signaling, contributes to hyperexcitability and acute seizures following TMEV infection. Pharmacotherapies designed to suppress TNFR1-mediated and/or to augment TNFR2-mediated effects of TNFα may provide antiseizure and disease modifying effects following CNS infection.

Significance Statement CNS infection is a significant etiology for the development of acquired epilepsy. Infection-induced uncontrolled inflammatory reaction in the brain can damage the parenchyma and contribute to acute seizures and the development of epilepsy. A large number of patients suffering from infection-induced epilepsy are pharmacoresistant to available antiseizure drugs. In the present study, we report that elevated level of tumor necrosis factor-α (TNFα), a key inflammatory cytokine, in the hippocampus following TMEV infection may mediate the excitotoxic effects through the TNFR1-mediated pathway and contribute to acute seizures. Our results suggest that selective inhibition of the TNFα-TNFR1 signaling may provide a new strategy to decrease acute seizures and potentially suppress the development of epilepsy.