Mechanisms of Hypoxia-Mediated Disturbances in Cerebral Maturation in a Fetal Ovine Model of Maternal Sleep Apnea

Project Summary Although sleep apnea arising from sleep-disordered breathing commonly occurs during pregnancy, the cumulative impact of brief repetitive episodes of maternal intermittent hypoxia (IHx) on fetal brain development is unknown. We have developed a novel clinically relevant model of maternal IHx, which reproducibly results in fetal systemic IHx early in the third trimester. The fetal hippocampus appears to be particularly sensitive to maternal IHx, which chronically disrupts neuronal activity and cellular mechanisms of learning and memory. Our over-riding hypothesis is that maternal IHx globally disrupts fetal cerebral development and results in persistent changes in postnatal learning and memory. In aim 1, we will first employ near infrared spectroscopy to define cerebral tissue hypoxemia in awake fetuses subjected to maternal IHx in utero. We will next determine the susceptibility of the fetal hippocampus to cell death, inflammation and white matter injury. We will also determine the impact of maternal IHx on disturbances in maturation of neuronal dendrites and spine density, which shape behaviorally important neural circuits, which regulate synaptic plasticity and neurotransmission during development. Complementary electrophysiological studies will determine the functional effects of IHx on synaptic transmission, long-term synaptic potentiation (LTP) and intrinsic excitability of hippocampal neurons to fire action potentials; which are all key cellular mechanisms that mediate learning and memory in vivo. Aim 2 will employ complementary advanced MRI and morphometric approaches to analyze the relative susceptibility of hippocampal-related brain regions to fetal IHx, which could inform future clinical studies by defining the global impact of maternal IHx on key brain regions required for optimal neurodevelopment and circuit formation. We will determine the spectrum of regional disturbances in fetal brain growth and maturation, cell death, inflammation and myelination and provide a quantitative analysis of differences in fetal brain volume differences. In aim 3, mechanistic fetal hippocampal studies will test the hypothesis that enhancing hippocampal synaptic transmission at CA3-CA1 synapses will reverse maternal IHx-mediated disturbances in fetal hippocampal synaptic plasticity, which underlie the developmental maturation of cellular mechanisms of learning and memory. We will determine in 3.1 the contribution of disturbances in AMPA and NMDA receptor subunit composition and expression levels to disturbances in glutamatergic synaptic transmission and LTP. In 3.2, we will determine the efficacy of an allosteric AMPA receptor agonist (ampakine) to strengthen synaptic transmission and plasticity in vitro. In 3.3, We will undertake pioneering neurobehavioral studies to determine if disrupted fetal hippocampal synaptic plasticity results in persistent hippocampal learning and memory deficits in juvenile lambs. Our long-term objectives are to define mechanisms through which maternal IHx disrupts fetal cerebral maturation and develop strategies to mitigate pregnancy-associated complications of maternal IHx on brain development, which may improve learning and memory.