Microglia involvement in the schizophrenia occurrence in male offspring with maternal dexamethasone exposure

Background: Fetal microglia are particularly sensitive cells to the changes in utero environment and show sex-biased differences in shape and function. Maternal stress hormone induction can affect fetal microglial functions including alterations in synaptic pruning and cytokine secretion. It may contribute to psychiatric outcomes in offspring such as schizophrenia and depression. Methods: : We administered a 50 µg/kg dexamethasone (DEX) to dams subcutaneously from gestational days 16 to 18. To characterize behaviors of maternal DEX exposed offspring, we assessed depressive-like and schizophrenia-relevant behaviors among 5 week old (adolescence), 10 week old (adult), and orchiectomized group respectively. Using quantitative real-time polymerase chain reaction, western blotting, and rapid Golgi staining, microglial morphology and synaptic pruning were assessed. Results: : Prenatal exposure to dexamethasone (PN-DEX) induced SCZ-relevant behavior in male mice and depressive-like behavior in female mice. SCZ-relevant behavioral patterns were induced in 10 week old (10 W) male mice but not in 5 week old (5 W) male mice. Microglia in the medial prefrontal cortex (mPFC) and the striatum (STR) of 10 W males prenatally treated with dexamethasone (10 W PN-DEX-M) showed hyper-ramified morphology and dramatically reduced spine density in mPFC. Immunofluorescence studies indicated that microglia in the mPFC of the 10 W PN-DEX-M group interacted with pre-synaptic Bassoon and post-synaptic density 95 (PSD95) puncta. PN-DEX-M also showed significantly changed dopamine system proteins. A testosterone surge was not observed in parallel to SCZ-relevant behavior in 10 W PN-DEX-M. Furthermore, females prenatally treated with dexamethasone (PN-DEX-F) displayed depressive-like behavior, in addition to HPA axis activation and inflammatory microglial phenotypes in their hippocampus (HPC). Conclusions: : Our study demonstrated that maternal DEX exposure induces sex-biased abnormal behavior as well as SCZ-relevant behavior in male offspring, and depressive-like behaviors in female offspring. We propose that altered microglial function, such as increased synaptic pruning, may be involved in the occurrence of SCZ-relevant behavior in PN-DEX-M and sex-biased abnormal behavior in the PN-DEX model.