The biology of microglia in neural development and synaptic maintenance in homeostatic and inflammatory conditions

Microglia, the innate immune cells of the brain, are not only immune surveyors, but also play important roles in neural development and maintenance. Microglial aberrations, including changes in morphology, gene expression, and phagocytic activity, have been observed in humans and animal models of pathologies involving cognitive and behavioral consequences. However, the precise contribution of microglial biology is not well characterized. Expression profiling of microglia and neural stem cells, co-culture assays, and transgenic mice were used to identify microglial micro-RNAs and genes, and study their roles in neural development. The results show that a specific micro-RNA, miR-155, participates in the neurogenic deficits induced by inflammation, and microglia-derived Wnt5a is essential for neural differentiation and maturation. This indicates the potential involvement of abnormal microglia in neurodevelopmental disorders such as autism spectrum disorders (ASDs). ASDs are group of debilitating disorders characterized by behavioral symptoms, including social and communication deficits and repetitive or restricted behaviors. I hypothesize that aberrant microglial biology plays a role in neurogenic and behavioral deficits in a mouse model of ASD. I performed a time-course study of microglial gene expression profiling, neural and microglial morphology, neurophysiology, and behavior in the maternal immune activation (MIA) model of ASD induced by the innate immunity ligand polyinosinic:polycytidylic acid. Microglia in MIA offspring displayed altered expression of 22 genes including 14 involved in cell-cell interaction, increased complexity of branching, and increased interactions with dendritic spines of cortical layer V pyramidal neurons. Microglial abnormalities were associated with neurophysiological alterations, measured by whole-cell patch clamp recordings, increased neuronal spine density, and ASD-like behaviors. MIA offspring treated with a colony stimulating factor -1 receptor inhibitor, to deplete and replenish microglia, showed correction of specific behaviors, microglial gene expression and branching, microglia-spine interactions, and spine density, and partial correction of neurophysiology. The data presented here shed new insight into the functional effects of microglia gene and microRNA expression in neurodevelopment. Furthermore, inflammation induces microglial aberrations that lead to altered neurodevelopment; this strongly supports the idea that targeting specific microglial genes and miRNAs will be a worthwhile approach to pursue for molecular intervention in ASD and related disorders.2018-11-02T00:00:00