Maternal sleep disordered breathing during pregnancy as a cause of autism relevant neuronal and behavioral aberrations in the offspring.

Abstract

Sleep disordered breathing (SDB) is characterized by recurring breathing cessations during sleep, causing intermittent hypoxia (oxygen deprivation) often several hundred times per night. SDB is present in ~15% of pregnant women as compared to ~2–4% of non‐pregnant women of childbearing age. Risk factors for gestational SDB development bear striking similarities to the collection of maternal risk factors for autism spectrum disorders (ASD), including advanced maternal age and maternal obesity. Maternal immune activation/inflammation is both a consequence of SDB, and an independent risk factor for, ASD. We posit that an overlooked, yet increasingly common inflammatory stimulus, maternal SDB, contributes to ASD etiology. We recently developed a rat model in which to study the consequences of maternal SDB on the offspring by exposing pregnant rats to nightly intermittent hypoxia from gestational days 10–21. Our findings indicate that offspring of mothers subjected to intermittent hypoxia during pregnancy exhibit deficits in several autism‐relevant behaviors, including a constellation of cognitive impairments, reduced interest in social interaction, and heightened anxiety. In most instances, the magnitude of behavioral disruption was more severe in male than female offspring. To begin to understand the mechanisms contributing to these behavioral aberrations, we examined the density of dendritic spines in the prefrontal cortex (PFC) and CA3 region of the hippocampus. Our data suggest that the offspring of mothers subjected to nightly intermittent hypoxia exhibited a striking increase in dendritic spine density in the PFC when compared to control offspring. However, the dendritic spine density in the CA3 region showed no significant differences between groups. Similar to our behavioral observations, dendritic spine aberrations were more prominent in male vs. female offspring. Additionally, these male offspring showed significant differences in spine morphology when compared to control offspring. Taken together, these findings indicate that maternal sleep disordered breathing not only induces autism‐relevant behavioral impairments, but also mimics the heightened cortical synaptic connectivity phenotypes recently uncovered in autism. Future studies are aimed at identifying a role for microglial inflammation and concomitant reduction in microglial‐mediated synaptic pruning in the behavioral and synaptic structural alterations that we have revealed in this model.Support or Funding InformationR25 Team‐ScienceUW2020 Pilot Award