Proinflammatory state of the brain increases the risk for seizure development. 
Neonatal Borna disease virus (BDV)-infection of mice with neuronal 
overexpression of tumor necrosis factor-α (TNF) was used to investigate the 
complex relationship between enhanced cytokine levels, neurotropic virus 
infection and reaction pattern of brain cells focusing on its role for seizure 
induction. Viral antigen and glial markers were visualized by 
immunohistochemistry. Different levels of TNF in the CNS were provided by the 
use of heterozygous and homozygous TNF overexpressing mice. Transgenic TNF, 
total TNF (native and transgenic), TNF-receptor (TNFR1, TNFR2), IL-1 and 
N-methyl-D-aspartate (NMDA)-receptor subunit 2B (NR2B) mRNA values were measured 
by real time RT-PCR. BDV-infection of TNF-transgenic mice resulted in 
non-purulent meningoencephalitis accompanied by epileptic seizures with a higher 
frequency in homozygous animals. This correlated with lower weight gain, 
stronger degree and progression of encephalitis and early, strong microglia 
activation in the TNF-transgenic mice, most obviously in homozygous animals. 
Activation of astroglia could be more intense and associated with an unusual 
hypertrophy in the transgenic mice. BDV-antigen distribution and infectivity in 
the CNS was comparable in TNF-transgenic and wild-type animals. Transgenic TNF 
mRNA-expression was restricted to forebrain regions as the transgene construct 
comprised the promoter of NMDA-receptor subunit2B and induced up-regulation of 
native TNF mRNA. Total TNF mRNA levels did not increase significantly after 
BDV-infection in the brain of transgenic mice but TNFR1, TNFR2 and IL-1 mRNA 
values, mainly in the TNF overexpressing brain areas. NR2B mRNA levels were not 
influenced by transgene expression or BDV-infection. Neuronal TNF-overexpression 
combined with BDV-infection leads to cytokine up-regulation, CNS inflammation 
and glial cell activation and confirmed the presensitizing effect of elevated 
cytokine levels for the development of spontaneous epileptic seizures when 
exposed to additional infectious noxi.