Impaired Oligodendrocyte Development Following Preterm Birth: Promoting GABAergic Action to Improve Outcomes

Abstract

Preterm birth is associated with poor long-term neurodevelopmental and behavioral outcomes, even in the absence of obvious brain injury at the time of birth. In particular, behavioral disorders characterized by inattention, social difficulties and anxiety are common among children and adolescents who were born moderately to late preterm (32-37 weeks' gestation). Diffuse deficits in white matter microstructure are thought to play a role in these poor outcomes with evidence suggesting that a failure of oligodendrocytes to mature and myelinate axons is responsible. However, there remains a major knowledge gap over the mechanisms by which preterm birth interrupts normal oligodendrocyte development. In utero neurodevelopment occurs in an inhibitory-dominant environment due to the action of placentally derived neurosteroids on the GABA_A receptor, thus promoting GABAergic inhibitory activity and maintaining the fetal behavioral state. Following preterm birth, and the subsequent premature exposure to the ex utero environment, this action of neurosteroids on GABA_A receptors is greatly reduced. Coinciding with a reduction in GABAergic inhibition, the preterm neonatal brain is also exposed to ex utero environmental insults such as periods of hypoxia and excessive glucocorticoid concentrations. Together, these insults may increase levels of the excitatory neurotransmitter glutamate in the developing brain and result in a shift in the balance of inhibitory: excitatory activity toward excitatory. This review will outline the normal development of oligodendrocytes, how it is disrupted under excitation-dominated conditions and highlight how shifting the balance back toward an inhibitory-dominated environment may improve outcomes.

Keywords: GABA; glutamate; neurosteroids; oligodendrocyte; preterm (birth).

Figure 1

Characterizing oligodendrocytes throughout the lineage. Oligodendrocytes originate from pre-progenitor (OPP) neural cells and are committed to the oligodendrocyte pathway under the influence of NKx2.2, Olig1/2, and Sox10. Once committed to the pathway, stage specific markers of oligodendrocytes allow for characterization of the lineage. Progenitor (OPC) and pre-oligodendrocytes (Pre-OL) feature stage-specific growth factor receptors (platelet derived growth factor receptor alpha; PDGFRα), surface antigens (neural/glial antigen 2; NG2) and cell adhesion molecules (polysialylated-neural cell adhesion molecule; PSA-NCAM), whilst premyelinating oligodendrocytes possess enzymes for lipid synthesis (galactocerebrosidase; GalC/O1). Finally, myelinating oligodendrocytes are characterized by the presence of myelin proteins such as myelin-associated glycoprotein (MAG), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP). Oligodendrocytes at this final stage of the lineage are the only ones capable of producing myelin and must also have contact with neuronal axons to perform this role. Figure created with BioRender.com.

Figure 2

Increased cortisol in the preterm neonate is associated with poor outcomes. Male guinea pigs born preterm (GA62; blue bars) have (A) higher salivary cortisol concentrations as a neonate (24 h old) and as a juvenile (corrected postnatal day 25), (B) decreased area coverage of myelin basic protein (MBP) in the CA1 region of the hippocampus, and (C) exhibit hyperactive behavior by spending more time mobile in the open field and inner zone when compared to term born (GA69; white bars) age-matched controls. Adapted from (34, 77). *p < 0.05, n = 4–10.

Figure 3

(A) The moderate to late gestation in utero neural environment is characterized by a dominance of GABAergic activity, which plays a key role in promoting oligodendrocyte maturation and myelination. (B) The preterm ex utero environment is characterized by a loss of GABAergic activity following a reduction in placental neurosteroid supply. Subsequently, this loss disrupts the fetal “sleep” state, and may also coincide with additional adverse insults, including excessive glucocorticoid concentrations and periods of hypoxia. The resulting increase in glutamate action increases the amount of calcium ions flowing into the oligodendrocyte, thus preventing its normal development and production of myelin. Figure created with BioRender.com.

Figure 4

Ganaxolone (GNX) 5 mg/kg by subcutaneous injection daily for 1 week following preterm birth restores mature myelin coverage in (A) the CA1 region of the hippocampus, and (B) the overlying subcortical white matter at childhood-equivalent age (corrected postnatal day 28). Behavior was also restored toward a term born phenotype for (C) the distance traveled, and (D) the time spent mobile in the open field arena. (*p < 0.05, n = 4–10). Adapted from (55).