Abstract Details

Title Novel In Vivo Model of Prenatal Hypoxic Injury and Genetic Mitochondrial Hyposufficiency

Topic Child Neurology and Developmental Neurology

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 7-056

Objective To study the interaction between in utero hypoxia and intrinsic ability to cope with metabolic stress.

Background Neonatal hypoxic ischemic encephalopathy (HIE) is a leading worldwide cause of brain injury resulting in neurodevelopmental disease. We hypothesize that symptom severity after HIE is influenced by an individual’s ability to cope with metabolic stress, particularly in cortical inhibitory interneurons that require mitochondrial ATP production during prenatal migration.

Design/Methods To test our hypothesis, we have developed a murine model of prenatal hypoxic injury and exposed mice lacking Ant1, a mitochondrial ATP transport protein, and control mice to 5% FiO₂ during late gestation (E16.5-E18.5) for up to 8 hours. Ant1-/- mice have disrupted prenatal interneuron migration but a mild adult phenotype. Pregnant mice were videotaped during hypoxic exposure to monitor survival and physiologic response. Two experiments were performed on offspring. First, fetal brains were harvested to determine the duration of hypoxia needed to induce a significant hypoxic response. Induction of Vegfa mRNA by hypoxia was used to characterize the hypoxic molecular response in the fetal brain. Second, offspring exposed to hypoxia were monitored postnatally for survival and growth.

Results Pregnant mice survive hypoxic exposure, but demonstrate marked attenuation of movement as FiO₂ is decreased. Prenatal hypoxic exposure of 4 hours induced a statistically significant increase of Vegfa in Ant1-/- and control mice. Importantly, Ant1-/- and control offspring survived after 4 hours of prenatal hypoxic exposure and had appropriate postnatal growth.

Conclusions These data suggest that murine prenatal hypoxic exposure is a viable model for studying the complex interactions between hypoxia and the placental and fetal responses contributing to injury of the developing brain. Furthermore, titration of prenatal hypoxia can be used to determine the dose effect of hypoxia on molecular and physiologic properties of different cell types in order to develop novel therapeutic interventions.

Authors/Disclosures
Ana G. Cristancho, MD, PhD (Children's Hospital of Philadelphia) PRESENTER	Dr. Cristancho has nothing to disclose.
Elyse Gadra (Children's Hospital of Philadelphia)	Ms. Gadra has nothing to disclose.
	No disclosure on file
Douglas C. Wallace (University of California - Irvine)	No disclosure on file
	No disclosure on file
Eric D. Marsh, MD, PhD (Children's Hospital of Philadlephia)	Dr. Marsh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia Pharmacuticals. Dr. Marsh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke Therapeutics. Dr. Marsh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia Pharmaceuticals. The institution of Dr. Marsh has received research support from NIH. The institution of Dr. Marsh has received research support from Rett Syndrome Research Trust. The institution of Dr. Marsh has received research support from International Rett Syndrome Foundation. The institution of Dr. Marsh has received research support from Eagles Autism Challenge. The institution of Dr. Marsh has received research support from LouLou Foundation. The institution of Dr. Marsh has received research support from International CDKL5 Resarch Foundation. The institution of Dr. Marsh has received research support from Acadia Pharmaceuticals. The institution of Dr. Marsh has received research support from Marinus. The institution of Dr. Marsh has received research support from Stoke Therapeutics. The institution of Dr. Marsh has received research support from Takeda Pharmaceuticals. Dr. Marsh has received personal compensation in the range of $500-$4,999 for serving as a Grant Review with NIH. Dr. Marsh has received personal compensation in the range of $5,000-$9,999 for serving as a Expert Witness with Department of Human Services. Dr. Marsh has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Medscape.

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