RT Journal Article
SR Electronic
T1 Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0105-17.2017
DO 10.1523/ENEURO.0105-17.2017
VO 4
IS 2
A1 Dipan C. Patel
A1 Glenna Wallis
A1 E. Jill Dahle
A1 Pallavi B. McElroy
A1 Kyle E. Thomson
A1 Raymond J. Tesi
A1 David E. Szymkowski
A1 Peter J. West
A1 Roy M. Smeal
A1 Manisha Patel
A1 Robert S. Fujinami
A1 H. Steve White
A1 Karen S. Wilcox
YR 2017
UL http://www.eneuro.org/content/4/2/ENEURO.0105-17.2017.abstract
AB 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.