Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA-damage in early postnatal brain

Cx3cr1CreER driven Cre-recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia and macrophages. However, an in-depth analysis for the possible detrimental effects of Cre-activity in microglia, surprisingly remains missing. Here we demonstrate an age-dependent sensitivity of microglia to Cx3cr1-Cre-toxicity, wherein Cre-induction specifically in early postnatal microglia is detrimental for microglial development, proliferation and function. Tamoxifen (TAM) induced Cre-activity leads to microglial activation, type1-interferon (IFN-1) signaling and increased phagocytosis, causing aberrant synaptic pruning during early postnatal period and anxiety behavior in later age. The detrimental effects of Cre-induction are caused due to DNA-damage induced toxicity in microglia, and is limited to the early postnatal period, showing no detrimental effects in adult microglia. Thus, our study reveals the age-dependent vulnerability of microglia to Cre-activity, thereby highlighting age-dependencies of Cre-action, which could be especially applicable in the broader context of environment-responsive cell-types. Overall design: Analysis of FACS-sorted microglia from Tamoxifen vs Vehicle treated neonatal brains of Cx3cr1-CreER positive mice