Tuberous Sclerosis Complex (TSC) is a genetic disorder associated with high rates of intellectual disability and autism. Although previous studies focused on the role of neuronal deficits in the memory phenotypes of rodent models of TSC, the results presented here demonstrate a role for microglia in these deficits. Mice with a heterozygous null mutation of the Tsc2 gene (Tsc2+/-), show deficits in hippocampal dependent tasks, as well as abnormal long-term potentiation (LTP) in the hippocampal CA1 region. Here, we show that microglia and type I interferon signaling (IFN1) have a key role in the object place recognition (OPR; a hippocampal dependent task) deficits and abnormal LTP of Tsc2+/- male mice. Unexpectedly, we demonstrate that male, but not female, Tsc2+/- mice showed OPR deficits. Importantly, these deficits can be rescued by depletion of microglia, as well as by a genetic manipulation of a signaling pathway known to modulate microglia function (interferon-alpha/beta receptor alpha chain null mutation). In addition to rescuing the OPR deficits, depletion of microglia also reversed the abnormal LTP of the Tsc2+/- mice. Altogether, our results suggest that altered IFN1 signaling in microglia cause the abnormal LTP and OPR deficits of male Tsc2+/- mice.
Defining the Role of Type I Interferon Signaling in the Increased Accumulation of Versican in Lungs of Mice Exposed to Influenza Infection
