Neurobiology of premature brain injury

Abstract

Every year in the United States, an estimated 500,000 babies are born preterm (before 37 completed weeks of gestation), and this number is rising, along with the recognition of brain injuries due to preterm delivery. A common underlying pathogenesis appears to be perinatal hypoxia induced by immature lung development, which causes injury to vulnerable neurons and glia. Abnormal growth and maturation of susceptible cell types, particularly neurons and oligodendrocytes, in preterm babies with very low birth weight is associated with decreased cerebral and cerebellar volumes and increases in cerebral ventricular size. Here we reconcile these observations with recent studies using models of perinatal hypoxia that show perturbations in the maturation and function of interneurons, oligodendrocytes and astroglia. Together, these findings suggest that the global mechanism by which perinatal hypoxia alters development is through a delay in maturation of affected cell types, including astroglia, oligodendroglia and neurons.

Figure 1

Chronic perinatal hypoxia causes a delay in maturation of interneurons. Top, relative time course of normal interneuron development (left) in the brains of both humans and rodents. Exposure to hypoxic injury (right) during the early postnatal period does not affect interneuron proliferation or migration but induces a delay of interneuron maturation and connectivity. Bottom, developmental pattern of interneuron antigen expression for parvalbumin (PrV), somatostatin (SST) and distal-less homeobox 2 (Dlx2) both under normal conditions (solid lines) and following hypoxic injury (dashed lines). Immature interneuron markers such as Dlx2 are unaffected by injury at this stage of development, but proteins upregulated with maturation such as PrV are vulnerable and show long-lasting perturbations in expression levels. For more details, see ref. .

Figure 2

Perinatal white matter injury causes delays in OLC maturation and in developmental myelination. Top, time course of oligodendroglia development and myelination in the human and rodent brain identifies a specific time window for risk of white matter injury. A perinatal insult causes a delay in OLC maturation and myelination. Middle, OLC lineage progression under normal physiological conditions. Antigenic markers identify distinct stages of OLC maturation from the OLC progenitor to the mature, myelinating OLC stage. OLC progenitors and pre-OLCs are most abundant during the developmental time window corresponding to high risk of white matter injury. Bottom, developmental regulation of major developmental markers at different stages of OLC lineage progression. Markers: PDGFR-α, platelet-derived growth factor receptor-α; A2B5, a cell surface ganglioside epitope expressed on oligodendrocyte progenitors; NG2, neuron-glial antigen 2; Olig1, oligodendrocyte transcription factor 1; Olig2, oligodendrocyte transcription factor 2; GPDH, glycerol-3-phosphate dehydrogenase; O1, oligodendrocyte antibody 1, a mature oligodendrocyte marker; O4, oligodendrocyte antibody 4, an immature oligodendrocyte marker; CNP, cyclic nucleotide phosphodiesterase; CC1, antibody that detects the APC (adenomatous polyposis coli) protein; Sox10, SRY-related HMG-box 10 transcription factor; GalC, galactocerebroside; MBP, myelin basic protein; PLP, proteolipid protein; MAG, myelin-associated glycoprotein; MOG, myelin oligodendrocyte glycoprotein.