Type I Interferon Receptor Signaling in Astrocytes Regulates Hippocampal Synaptic Plasticity and Cognitive Function of the Healthy CNS

Type I interferon receptor (IFNAR) signaling is a hallmark of viral control and host protection. Here, we show that, in the hippocampus of healthy IFNAR-deficient mice, synapse number and synaptic plasticity, as well as spatial learning, are impaired. This is also the case for IFN-β-deficient animals. Moreover, antibody-mediated IFNAR blocking acutely interferes with neuronal plasticity, whereas a low-dose application of IFN-β has a positive effect on dendritic spine structure. Interfering with IFNAR signaling in different cell types shows a role for cognitive function and synaptic plasticity specifically mediated by astrocytes. Intriguingly, levels of the astrocytic glutamate-aspartate transporter (GLAST) are reduced significantly upon IFN-β treatment and increase following inhibition of IFNAR signaling. These results indicate that, besides the prominent role for host defense, IFNAR is important for synaptic plasticity as well as cognitive function. Astrocytes are at the center stage of this so-far-unknown signaling cascade. [Display omitted] •Baseline levels of IFNAR signaling are critical for synaptic plasticity•IFNAR signaling is needed acutely during synaptic plasticity•Astrocyte IFNAR signaling may regulate synaptic plasticity by GLAST modulation Interferon (IFN) signaling within the CNS is critical for synaptic plasticity and processes of learning and memory formation under physiological conditions. Hosseini et al. provide evidence that the type I IFN receptor (IFNAR) is mediating this effect via the glutamate-aspartate transporter (GLAST) in astrocytes by regulating synaptic glutamate levels.