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Mouse intermittent hypoxia mimicking apnoea of prematurity: effects on myelinogenesis and axonal maturation
Jun Cai1, Chi Minh Tuong, Yiping Zhang
1Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA. j0cai002@louisville.edu
Insights
Neonatal intermittent hypoxia impairs white matter development in preterm infants, leading to hypomyelination and axonal deficits. These changes may contribute to long-term neurobehavioral issues in premature babies.
Area of Science:
- Neuroscience
- Developmental Biology
- Neonatal Medicine
Background:
- Premature infants face risks of infantile apnea and neurodevelopmental deficits.
- White matter abnormalities in preterm neonates predict poor cognitive outcomes.
- Oligodendrocyte maturation and myelination are crucial during late gestation and early infancy.
Purpose of the Study:
- To investigate the impact of intermittent hypoxia on oligodendroglia and axon development in neonatal mice.
- To determine if infantile apnea-like conditions exacerbate white matter impairments in early brain development.
Main Methods:
- A neonatal mouse model exposed to intermittent hypoxia (postnatal days 2-10).
- Analysis of myelin protein expression (MBP, PLP, MAG, CNPase).
- Ultrastructural examination of myelin sheath and axons, assessing neurofilament and microtubule components.
Main Results:
- Intermittent hypoxia caused region-selective hypomyelination in key brain areas (corpus callosum, striatum, fornix, cerebellum).
- Decreased myelin protein expression and arrested oligodendrocyte maturation were observed.
- Axonal immaturity and deficits in axonogenesis/synaptogenesis were evident, with immature oligodendrocytes being more vulnerable.
Conclusions:
- Neonatal intermittent hypoxia induces significant white matter impairments, including hypomyelination and axonal deficits.
- These structural changes are linked to electrophysiological alterations, potentially underlying long-term neurobehavioral sequelae.
- The findings highlight the vulnerability of developing white matter to hypoxic insults during critical neonatal periods.
Abstract:
Premature babies are at high risk for both infantile apnoea and long-term neurobehavioural deficits. Recent studies suggest that diffuse structural changes in brain white matter are a positive predictor of poor cognitive outcomes. Since oligodendrocyte maturation, myelination, axon development, and synapse formation mainly occur in the third trimester of gestation and first postnatal year, infantile apnoea could lead to and/or exaggerate white matter impairments in preterm neonates. Therefore, we investigated oligodendroglia and axon development in a neonatal mouse model of intermittent hypoxia between postnatal days 2 and 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix, and cerebellum, but not in the pons or spinal cord. Intermittent hypoxia-elicited alterations in myelin-forming processes were reflected by decreased expression of myelin proteins, including MBP, PLP, MAG, and CNPase, possibly due to arrested maturation of oligodendrocytes. Ultrastructural abnormalities were apparent in the myelin sheath and axon. Immature oligodendrocytes were more vulnerable to neonatal intermittent hypoxia exposures than developing axons, suggesting that hypomyelination may contribute, at least partially, to axonal deficits. Insufficient neurofilament synthesis with anomalous components of neurofilament subunits, β-tubulin, and MAP2 isoforms indicated immaturity of axons in intermittent hypoxia-exposed mouse brains. In addition, down-regulation of synapsin I, synaptophysin, and Gap-43 phosphorylation suggested a potential stunt in axonogenesis and synaptogenesis. The region-selective and complex impairment in brain white matter induced by intermittent hypoxia was further associated with electrophysiological changes that may underlie long-term neurobehavioural sequelae.
