Maternal Breathing Dysfunction During Pregnancy Alters Microglial Activities And Increases Risk For Psychiatric Disorders In Her Offspring

Each year, over half a million women develop sleep disordered breathing (SDB) by the third trimester, the prevalence of which is increasing in parallel with the obesity epidemic. While negative consequences of SDB during pregnancy on the health of the mother and newborn are becoming better appreciated, nothing is known about the impact of SDB on the neural function of her offspring. SDB is a potent inflammatory stimulus, inducing chronic inflammation that contributes to many of the morbidities associated with SDB. Since epidemiological studies suggest that maternal inflammation is associated with the development of neuropsychiatric disorders in her offspring, we tested the hypothesis that in utero intermittent hypoxia impairs cognitive behavior in the offspring. Pregnant rat dams were exposed to chronic intermittent hypoxia (8 hrs/day, 2 min 10.5% O2 separated by 2 min of 21% O2) or normoxia from gestation days 10–21 (GIH and GNX, respectively). Juvenile (3 week) and adult (8 week) offspring were tested in a Y‐maze spontaneous alternation task, a well‐validated index of spatial working memory. We found that spontaneous alternation performance was severely impaired in juvenile and adult male GIH offspring relative to GNX offspring, suggesting GIH results in early developmental emergence of working memory impairments. In contrast, female GIH offspring did not exhibit impairments in spatial working memory at either age. Microglia isolated from the forebrain of male GIH offspring exhibited significant reductions in the expression of the phagocytic receptor gene complement receptor 3 (CD11b), suggesting that GIH impairs microglial synaptic pruning activities. In the same samples, expression levels of DNA methyltransferase enzymes (DNMTs), that are responsible for repressing gene expression, were increased. Since hypoxia enriches the transcriptional activation mark H3K4me3 in microglial cultures, we hypothesize that GIH upregulates DNMT gene expression via epigenetic histone alterations to fetal microglia, which represses microglial phagocytic gene expression. Together, these data suggest that GIH: 1) sex‐dependently alters cognitive phenotypes in GIH offspring, and 2) may induce epigenetic suppression of microglial phagocytic activities that impair microglial synaptic pruning during development, altering forebrain synaptic connectivity in male offspring.Support or Funding InformationSupported by R01 NS085226 (JJW) and HL105511 (TLB)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.