Poly(I:C)-induced long-term behavioral deficits are accompanied by epigenetic changes in microglia of male mice (ChIP-seq)

While the exact mechanisms for a sex bias in the development of neuropsychiatric disorders remain only vaguely understood, there is increasing evidence that an early life immune activation contributes to the disease pathogenesis. By administering the double stranded RNA analogue polyriboinosinic:polyribocytidilic acid (poly(I:C)) we mimicked an early viral infection in neonatal female and male mice. As a consequence, male adolescent mice presented long-term behavioral deficits including impaired social behavior and defective spatial working and recognition memory. Notably, behavioral changes were completely absent in female mice. In male mice, poly(I:C) led to an increased number of infiltrating T cells in the brain parenchyma, an enhanced interferon-g (IFNg) signaling, and an epigenetic reprogramming of microglial cells. These reprogrammed microglial cells showed increased phagocytic activity, which resulted in the excessive loss of dendritic spines in male mice only. We corroborated these findings in a murine neonatal infection of mice with murine cytomegalovirus (MCMV) and found sustained aversive behavioral effects and a lower number of excitatory synapses within the hippocampal brain region in young adult male, but not in female mice. Together, our results highlight the crucial role of the early postnatal period for normal brain development: identical immune stimulation during this period led to distinct sex-specific long-term behavioral deficits, indicating that sex is potentially an underappreciated factor when investigating neuropsychiatric disorders. Overall design: We evaluated H3k4me3 and H3k9ac in microglia isolated from P40 male and female mice, which were poly(I:C) or vehicle-injected at P2-P6. There were 3 samples as a single replicate per group with input DNA as control. The sequencing was performed as a paired end design.