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Role of IFN‐γ in an experimental murine model of West Nile virus‐induced seizures
Author(s) -
Getts Daniel R.,
Matsumoto Izuru,
Müller Marcus,
Getts Meghann Teague,
Radford Jane,
Shrestha Bimmi,
Campbell Iain L.,
King Nicholas J. C.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04798.x
Subject(s) - kainic acid , encephalitis , seizure threshold , nmda receptor , interferon , amygdala , epilepsy , central nervous system , convulsion , immunology , biology , tumor necrosis factor alpha , virus , receptor , medicine , neuroscience , glutamate receptor , anticonvulsant
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)‐γ‐deficient (IFN‐γ −/− ) 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‐γ −/− mice reconstituted with IFN‐γ‐producing leukocytes showed that IFN‐γ is not required during central nervous system infection for limbic seizure development, suggesting a role for IFN‐γ 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‐γ −/− mice. Furthermore, NMDA‐receptor blockade with MK‐801 in WNV‐infected C57BL/6 mice abrogated seizures and prolonged survival. Our data show that IFN‐γ 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.