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

eNeuro. 2017 May 9;4(2):ENEURO.0105-17.2017. doi: 10.1523/ENEURO.0105-17.2017. eCollection Mar-Apr 2017.

Abstract

Central nervous system 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 that 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 after 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, after 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. Although 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 after 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 by TNFα signaling, contributes to hyperexcitability and acute seizures after TMEV infection. Pharmacotherapies designed to suppress TNFR1-mediated or augment TNFR2-mediated effects of TNFα may provide antiseizure and disease-modifying effects after central nervous system infection.

Keywords: AMPAR; TMEV; TNFR; TNFα; XPro1595; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Disease Models, Animal
  • Epilepsy, Temporal Lobe / virology
  • Hippocampus / metabolism*
  • Hippocampus / virology
  • Mice, Inbred C57BL
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Seizures / metabolism*
  • Seizures / pathology
  • Seizures / virology
  • Signal Transduction
  • Temporal Lobe / pathology
  • Theilovirus
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha