Role of IFN-gamma in an experimental murine model of West Nile virus-induced seizures.

Seizures are a major complication of viral encephalitis. However, the mechanisms of seizure-associated neuronal dysfunction remain poorly understood. We report that intranasal inoculation with West Nile virus (WNV) (Sarafend) causes limbic seizures in C57BL/6 mice, but not in interferon (IFN)-gamma-deficient (IFN-gamma-/-) mice. Both strains showed similar levels of virus in the brain, as well as similar concentrations of the cytokines, tumor necrosis factor and interleukin-6, both of which can alter neuronal excitability. Experiments in chimeric IFN-gamma-/- mice reconstituted with IFN-gamma-producing leukocytes showed that IFN-gamma is not required during central nervous system infection for limbic seizure development, suggesting a role for IFN-gamma in the developing brain. This was supported responses to pentylenetetrazole, kainic acid (KA), and N-methyl-d-aspartate (NMDA). Both strains of mice exhibited similar behavior after pentylenetetrazole challenge. However, while NMDA and KA treatment resulted in characteristic seizures in C57BL/6 mice, these responses were diminished (NMDA treatment) or absent (KA treatment) in IFN-gamma-/- mice. Furthermore, NMDA-receptor blockade with MK-801 in WNV-infected C57BL/6 mice abrogated seizures and prolonged survival. Our data show that IFN-gamma plays an important role in the development of the excitatory seizure pathways in the brain and that these cascades become pathogenic in encephalitic WNV infection.