Fatal neurological syndromes can occur after Measles virus (MeV) infection of the brain. The mechanisms controlling MeV spread within the central nervous system (CNS) remain poorly understood. We analyzed the role of type I interferon (IFN-I) receptor (IFNAR) signaling in the control of MeV infection in a murine model of brain infection. Using organotypic brain cultures (OBC) from wild-type and IFNARko 31 transgenic mice ubiquitously expressing the human SLAM (CD150) receptor, 32 the heterogeneity of the permissiveness of different CNS cell types to MeV infection was characterized. In the absence of IFNAR signaling, MeV propagates significantly better in explant slices. In OBC from IFNAR competent mice, while astrocytes and microglia were infected on the day of explant preparation, they became refractory to infection with time, in contrast to neurons and oligodendrocytes that remained permissive to infection. This selective loss of permissiveness to MeV infection was not observed in IFNARko OBC. Accordingly, the development of astrogliosis related to the OBC procedure was exacerbated in the presence of IFNAR signaling. In the hippocampus, this astrogliosis was characterized by a change in astrocyte phenotype and by an increase of IFN-I transcripts. A proteome analysis showed the up-regulation of 84 out of 111 secreted proteins. In the absence of IFNAR, only 27 secreted proteins were up-regulated, none of which were associated with antiviral activities. Our results highlight the essential role of the IFN-I response in astrogliosis and in the permissiveness of astrocytes and microglia that could control MeV propagation throughout the CNS. [ABSTRACT FROM AUTHOR]