Microglia are established early during embryonic development from precursors with erythro-myeloid potential that arise independent from definitive hematopoiesis. The cells subsequently persist throughout adulthood due to their longevity and self-renewal potential. Recent elegant work in zebra fish and mice has shown that microglia contribute in the embryo and during the early post-natal period actively to axon guidance and the pruning of excess neuronal synapses. These activities are associated with pronounced microglial activation and signs of physiological ‘sterile’ inflammation. In stark contrast, adult microglia display a robust state of quiescence that resists activation. These distinct activation states of microglia of the developing and adult brain are reflected in highly distinct gene expression signatures. Here, we intend to use an advanced fate mapping approach to investigate, if a fraction of adult microglia derives from cells that underwent transient activation during development or alternatively, arise from cells that retained quiescence through the developmental embryonic activation period. Specifically, we will employ a novel two component ‘split’ Cre system to permanently mark and label microglia that underwent activation, as indicated by their in situ IFN or IL-1 exposure (using CX3CR1-promoter driven C-Cre and N-Cre expression driven by a promoter induced upon activation). Labeled cells will be isolated and subjected to transcriptome and epigenome profiling to define the impact of the early developmental trauma on the adult microglia signature. In a broader context, our study aims to probe the existence of ‘microglial memory’. Epidemiological studies have shown an association between maternal infection and schizophrenia or autism in the progeny. Moreover, this observation has been reproduced in small animals studies that established that following maternal immune activation (MIA) offspring displays signs of autism spectrum disorder (ASD). MIA has been proposed to result in microglial priming and the persistent microglia might represent a critical causal link between the early trauma and the delayed neuronal dysfunctions and behavioral phenotypes observed in the adult or aged offspring. To specifically investigate the role of microglia in MIA, we will challenge mice that harbor the stimulus-sensitive reporter system during pregnancy with a poly(I:C) challenge and investigate the impact on the microglia compartment.