Several neurotropic viruses such as vesicular stomatitis virus (VSV) induce peripheral neutralizing Ab responses and still can infect cells within the CNS. To address whether local type I IFN receptor (IFNAR) triggering plays a role in controlling virus replication within the brain, we generated mice with a cell type-specific IFNAR deletion in neuroectodermal cells of the CNS (NesCre(+/-)IFNAR(flox/flox)). Intranasal VSV infection with 10(3) PFU was well tolerated by wild-type mice, whereas conventional IFNAR(-/-) mice died within 2-3 days. In contrast, brain-specific NesCre(+/-)IFNAR(flox/flox) mice survived until day 5-6 and then became hemiplegic and died. Terminally ill NesCre(+/-)IFNAR(flox/flox) mice showed 10- to 100-fold higher virus loads in the brain than IFNAR(-/-) mice, whereas little or no virus was found in other organs. In wild-type animals, virus could be reisolated only from the olfactory bulb until day 6 where also STAT1 activation as a measure of IFNAR triggering was detected. Virus infection was found exclusively in glomerular structures of the olfactory bulb, whereas surrounding cells that showed STAT1 phosphorylation as a measure of IFNAR trigging were free of virus. Our data indicate that upon intranasal VSV instillation, early and localized IFNAR triggering in the glomerular layer of the olfactory bulb is critically required to prevent viral spread over the entire CNS and thus confers survival.