Abnormal neurogenesis and cortical growth in congenital heart disease

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.

Microstructural Alterations and Oligodendrocyte Dysmaturation in White Matter After Cardiopulmonary Bypass in a Juvenile Porcine Model

“…Our recent study has identified several pathological signatures of the fetal human brain with CHD that can be reproduced and modeled with the developing piglet brain under chronic hypoxia. 20 A combined experimental paradigm using piglets exposed to both hypoxia and CPB will allow us to investigate the overall impact of CHD and subsequent cardiac surgery and will help further understanding of multietiological complex WM dysmaturation in the CHD population.…”

“…In the human brain WM occupies ≈50% of the total brain volume, whereas in rodents it is only 15% . In contrast the piglet brain is a powerful model to study human brain development as it displays a highly evolved, gyrencephalic neocortex structurally similar to the human brain . Furthermore ≈50% of the piglet brain volume is represented by WM .…”

“…19 In contrast the piglet brain is a powerful model to study human brain development as it displays a highly evolved, gyrencephalic neocortex structurally similar to the human brain. 20 Furthermore %50% of the piglet brain volume is represented by WM. 21 Finally the piglet is large enough in the newborn period for investigation using cardiopulmonary bypass (CPB), 22,23 which can result in unique and specific pathological conditions in the developing brain with CHD.…”

Ferret brain possesses young interneuron collections equivalent to human postnatal migratory streams

“…Like humans, and unlike rodents, they possess a gyrencephalic cortex (Barnette et al, ; Duque & McCormick, ; Johnson et al, ). Furthermore, they undergo extensive postnatal brain development (McConnell, , ; Morton et al, ). The ferret also captures other features specific to human brain, such as the presence of an outer sub‐ventricular zone (oSVZ; Gertz, Lui, LaMonica, Wang, & Kriegstein, ; Martínez‐Martínez et al, ; Reillo & Borrell, ).…”

Recent innovations in perfusion and cardiopulmonary bypass for neonatal and infant cardiac surgery

“…It is suggested this may be related to abnormal neurogenesis from a decrease in cerebral oxygen delivery during gestation and is positively associated with decreased brain volume and decreased gyrification (67). Thus, monitoring and assessment of neurologic function in the pediatric patient is paramount.…”