PROJECT SUMMARY
The fundamental hypothesis driving this exploratory R21 (FOA PA-21-200) is that maternal sleep apnea during
pregnancy causes maternal immune activation (MIA), resulting in multiple cognitive and social deficits that
emerge in juvenile stages and persist into adulthood. Sleep apnea is characterized by recurrent partial or
complete cessation of breathing during sleep that causes pathologic drops in blood oxygen levels (intermittent
hypoxia; IH), often hundreds of times each night. Each year, over half a million women have untreated sleep
apnea during pregnancy, in part due to insufficient screening, or a lack of patient compliance to sleep apnea
therapy. Although detrimental effects of maternal sleep apnea during pregnancy on the perinatal health of the
mother and her newborn have recently become appreciated, little is known about the impact of maternal SA on
the long-lasting health of her offspring. We developed an experimental model of sleep apnea in pregnancy by
exposing pregnant rats to a pattern of IH that mimics sleep apnea in humans. Our findings indicate that offspring
exposed to intermittent hypoxia during gestation (GIH) exhibit significant increases in neuronal spine density in
the medial prefrontal cortex, and behavioral impairments, including memory and social deficits that manifest in
juveniles, and persist into adulthood. Strikingly, GIH-induced behavioral deficits are more prominent in male
offspring whereas females are only slightly (or not at all) affected. Although the revealed behavioral deficits
individually typify several neuropsychiatric disorders of relevance to human health, the combination of enhanced
cortical synaptic connectivity, the early onset and persistence of behavioral dysfunction, and the comparative
severity of phenotypes in males suggests a possible autism-relevancy to our findings. Evidence indicates that
MIA during pregnancy is associated with increased offspring risk of autism spectrum disorder. In this proposal,
we will begin to test the hypothesis that maternal sleep apnea during pregnancy induces activation of the
maternal immune response that is a key initiator of the ensuing neuronal and behavioral impairments in her
offspring. IH causes chronic inflammation in humans and animal models, and it underlies much of the pathology
associated with sleep apnea in non-pregnant individuals. Intriguingly, many of the cytokines increased by sleep
apnea are the same as those associated with offspring neurological dysfunction in models of MIA.
Our preliminary data indicate that GIH upregulates IL-17a in the GIH male (but not female) placenta and in
maternal serum, a cytokine well known to orchestrate autism-like behaviors in offspring of mothers exposed
to other models of MIA. Our data therefore suggest that GIH may be an unrecognized trigger for MIA that
leads to a constellation of deficits in offspring that resemble behavioral and synaptic abnormalities in
humans with autism spectrum disorder. They also point to IL-17a as the culprit. If our hypotheses
are correct, our findings would be transformative and would inform physicians and patients alike to
perform early and consistent screening for SA in pregnancy to minimize neural damage to the unborn baby.
