Abstracts

Rationale: Virus infections of the central nervous system (CNS) can result in acute seizures. About 20% of patients who have had viral encephalitis go on to develop epilepsy. We have established a mouse model where about 50% of infected mice have behavioral seizures and recover. After a variable latent period mice go on to develop recurrent spontaneous seizures. We previously showed that the innate immune response to virus infection in the CNS plays a role in the development of seizures and epilepsy. Micro-RNAs (miRNAs) have various effects on CNS development and are involved in the modulation of innate immune responses. Various studies have demonstrated that miRNAs are up-regulated in human resected brain tissue from individuals with epilepsy. We have initiated studies investigating two miRNAs, miRNA-155 and miRNA-146a. MiRNA-155 has been reported to enhance inflammatory responses. In contrast miRNA-146a dampens inflammatory responses. Methods: C57BL/6 (B6) mice deficient in miRNA-155 (miRNA-155 KO), miRNA-146a (miRNA-146a KO) or wild-type mice were infected with 2x10⁵ plaque forming units (PFUs) of the DA strain of Theiler's murine encephalomyelitis virus (TMEV). Mice were weighed daily and monitored for behavioral seizures randomly during the workday for 21 days post infection (p.i.). The infected wild-type B6 mice develop acute behavioral seizures between day 3 and day 10 post infection. Results: We found that following TMEV infection with 2x10⁵ PFUs, about 50% of wild-type B6 mice experienced behavioral seizures between days 3-10 p.i. Unexpectedly, there was no difference between the numbers of the miRNA-155 KO mice developing seizures. In contrast, significantly fewer TMEV-infected miRNA-146a mice developed seizures. Conclusions: In an animal model for epilepsy, deletion of miRNA-155, a proinflammatory micro-RNA had no effect on the numbers of mice developing behavioral seizures compared to wild-type B6 mice, whereas fewer infected miRNA-146a (anti-inflammatory) depleted mice had seizures compared to wild-type B6 mice. This is contrary to what we would have predicted. We are exploring the basis for the differences.