Impaired Oligodendrocyte Development Following Preterm Birth: Promoting GABAergic Action to Improve Outcomes
Julia C Shaw1,2, Gabrielle K Crombie1,2, Hannah K Palliser1,2
1School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.
Insights
Preterm birth disrupts oligodendrocyte development, leading to behavioral issues. Shifting the brain
Area of Science:
- Neuroscience
- Developmental Biology
- Perinatal Medicine
Background:
- Preterm birth is linked to long-term neurodevelopmental and behavioral problems, including attention deficits, social difficulties, and anxiety.
- White matter microstructure deficits, particularly impaired oligodendrocyte maturation and myelination, are implicated in these poor outcomes.
- The mechanisms disrupting oligodendrocyte development following preterm birth are not fully understood.
Purpose of the Study:
- To review normal oligodendrocyte development.
- To examine how preterm birth disrupts oligodendrocyte development.
- To highlight potential therapeutic strategies targeting the inhibitory-excitatory balance.
Main Methods:
- Literature review of studies on neurosteroid action, GABAergic inhibition, and oligodendrocyte development in the context of preterm birth.
- Analysis of the impact of the ex utero environment on neurodevelopment.
- Discussion of the shift in inhibitory-excitatory balance due to environmental insults.
Main Results:
- In utero, neurosteroids promote an inhibitory environment crucial for fetal neurodevelopment via GABAA receptors.
- Preterm birth reduces neurosteroid action, decreasing GABAergic inhibition and exposing the brain to insults like hypoxia and glucocorticoids.
- These insults can increase glutamate, shifting the brain's balance towards excitation, which impairs oligodendrocyte development.
Conclusions:
- Preterm birth disrupts the critical inhibitory balance in the neonatal brain, hindering oligodendrocyte maturation.
- This shift towards excitation may underlie the observed neurodevelopmental and behavioral deficits.
- Restoring an inhibitory-dominant environment could be a promising therapeutic approach to improve outcomes for preterm infants.
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 GABAA 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 GABAA 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.
