CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner.

Abstract

Mutations in CHD8 (chromodomain-helicase-DNA binding protein 8) are highly associated with autism spectrum disorders. It has been well established that CHD8 has a prominent role in the development of neurons. However, there is little knowledge of its specific roles in microglia, and its possible roles in cellular functions after development, i.e. adulthood. In addition, while microglial dysfunction has been characterized in autism, the roles of autism-associated genes in microglial function have not been well characterized. Using conditional knockdown technology in C57BL6 mice models, we determined that adulthood deletion of Chd8 in microglia induces robust changes in behavior, including anxiety, social deficits, and depression-like behavior, in association with changes in microglial activation and robust microglial gene expression changes in the whole brain, including expression of cytokines. Of great interest, many of these changes were seen specifically in male deletion mice, and not female deletion mice. In contrast, adulthood neuron knockdown had more subtle effects on behavior, mainly on depression-like behavior in males. In addition, neuronal knockdown leads to upregulation of genes associated with Hedgehog and Wnt/Beta-catenin pathways in the hippocampus specifically in males. In summary, CHD8 is particularly important for microglial function in adulthood and has cellular effects that are specific to males in C57BL6 mice.