Early life stress perturbs the function of microglia in the developing rodent brain: New insights and future challenges

The role of the innate immune system in mediating some of the consequences of childhood abuse and neglect has received increasing attention in recent years. Most of the work to date has focused on the role that neuroinflammation plays in the long-term adult psychiatric and medical complications associated with childhood maltreatment. The effects of stress-induced neuroinflammation on neurodevelopment have received little attention because until recently this issue has not been studied systematically in animal models of early life stress. The primary goal of this review is to explore the hypothesis that elevated corticosterone during the first weeks of life in mice exposed to brief daily separation (BDS), which is a mouse model of early life stress, disrupts microglial function during a critical period of brain development. We propose that perturbations of microglial function lead to abnormal maturation of several neuronal and non-neuronal cellular processes resulting in behavioral abnormalities that emerge during the juvenile period and persist in adulthood. Here, we highlight recent work demonstrating that exposure to BDS alters microglial cell number, morphology, phagocytic activity, and gene expression in the developing hippocampus in a manner that extends into the juvenile period. These changes in microglial function are associated with abnormalities in developmental processes mediated by microglia including synaptogenesis, synaptic pruning, axonal growth, and myelination. We examine the changes in microglial gene expression in the context of previous work demonstrating developmental and behavioral abnormalities in BDS mice and in other animal models of early life stress. The possible utility of these findings for developing novel PET imaging to assess microglial function in individuals exposed to childhood maltreatment is also discussed.