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 ...