Research ArticleBrain Development

Abnormal neurogenesis and cortical growth in congenital heart disease

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Science Translational Medicine  25 Jan 2017:
Vol. 9, Issue 374, eaah7029
DOI: 10.1126/scitranslmed.aah7029

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Getting to the heart of the matter in brain development

Congenital heart disease (CHD), the most common birth defect in newborns, can be associated with developmental delays. Although reduced blood flow, genetic factors, and brain injury are thought to contribute, the cellular mechanisms underlying abnormal brain development due to CHD are unclear. Morton et al. used a piglet model of neonatal hypoxia to study the relationship between neural stem/progenitor cells and cortical development. Chronic hypoxia reduced the number of stem/progenitor cells within the subventricular zone in piglet brains, which limited the number of interneurons and cortical growth. These findings were also seen in brain tissue from human infants with CHD.

Abstract

Long-term neurological deficits due to immature cortical development are emerging as a major challenge in congenital heart disease (CHD). However, cellular mechanisms underlying dysregulation of perinatal corticogenesis in CHD remain elusive. The subventricular zone (SVZ) represents the largest postnatal niche of neural stem/progenitor cells (NSPCs). We show that the piglet SVZ resembles its human counterpart and displays robust postnatal neurogenesis. We present evidence that SVZ NSPCs migrate to the frontal cortex and differentiate into interneurons in a region-specific manner. Hypoxic exposure of the gyrencephalic piglet brain recapitulates CHD-induced impaired cortical development. Hypoxia reduces proliferation and neurogenesis in the SVZ, which is accompanied by reduced cortical growth. We demonstrate a similar reduction in neuroblasts within the SVZ of human infants born with CHD. Our findings demonstrate that SVZ NSPCs contribute to perinatal corticogenesis and suggest that restoration of SVZ NSPCs’ neurogenic potential is a candidate therapeutic target for improving cortical growth in CHD.

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