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.

Grant Number: 5R01HL163517-03
NIH Institute/Center: NIH
Principal Investigator: Stephen Back