Poster #105 - Sabrina DaSilva

Lasting mitochondrial and epigenetic disruption after prenatal hypoxia in glutamatergic neurons

DaSilva, Sabrina, MS (1,2), Cassidy, Margaret M., BA (1), Gadra, Ethan, BS (1), Smith, Maddie, BA (1), Cristancho, Ana G., MD, PhD (1,3) (1) Division of Child Neurology, Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA (2) Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA (3) Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

Prenatal hypoxia is a major cause of lifelong neurodevelopmental disabilities. Currently, the only specific intervention is therapeutic hypothermia, which is limited to a subset of patients and often fails to prevent long-term deficits. Understanding how a transient prenatal hypoxic insult leads to persistent neurological abnormalities is critical for developing more effective interventions. Using a mouse model of late gestation transient prenatal hypoxia, we previously found that this model phenocopies mild hypoxia, showing no early brain cell death immediately after exposure, but leading to disrupted synaptic structure and function in glutamatergic neurons in juveniles and multiple long-term functional deficits in adults. To uncover the mechanisms driving these persistent deficits, we conducted joint single nucleus RNA and ATAC sequencing of the cingulate cortex from juvenile mice (postnatal day 25-30) one month after prenatal hypoxia. Surprisingly, we found persistent repression of the mitochondrial function transcriptome. These changes correlate with decreased function of mitochondrial respiratory chain complexes I, II, and IV, and increased reactive oxygen species production in cortical homogenates. Furthermore, regions with reduced chromatin accessibility after prenatal hypoxia are enriched for the Nrf1 motif, a master regulator of mitochondrial biogenesis and function. Emerging evidence suggests that disruption of the epigenome is a critical consequence of prenatal brain injuries, including hypoxia. As Nrf1 binding is sensitive to DNA methylation, we are currently testing whether DNA methylation is variably disrupted after prenatal hypoxia, contributing to abnormal distribution of Nrf1 binding and abnormal mitochondrial gene expression and function in glutamatergic neurons. Together, these multiomic and functional data suggest that mitochondrial dysfunction persists in juvenile mice one month after transient prenatal hypoxia. These findings raise the possibility that mitochondria may serve as a long-term site of injury following early hypoxic insult. Targeting mitochondrial dysregulation may allow restoration of neuronal maturation to improve neurodevelopmental deficits from prenatal hypoxia.