Mouse intermittent hypoxia mimicking apnoea of prematurity: effects on myelinogenesis and axonal maturation

Abstract

Premature babies are at high risk for both infantile apnea and long-term neurobehavioral 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 3rd trimester of gestation and 1st postnatal year, infantile apnea 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 to 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix and cerebellum, but not 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. Ultra-structural 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 neurobehavioral sequelae.

Mild intermittent hypoxemia in neonatal mice causes permanent neurofunctional deficit and white matter hypomyelination

“…To test this hypothesis we developed a mouse model where WMI was induced by non-lethal IH stress and the phenotype was characterized by cerebral hypomyelination associated with permanent neurofunctional deficit, without cell degeneration in the brain. In contrast to reported models of WMI induced by IH mimicking severe hypoxemic event associated with apnea of prematurity (Cai et al, 2012;Oorschot et al, 2013), our paradigm of IH simulates only mild, non-bradycardia-associated, repetitive hypoxemic episodes, the IH-pattern of unknown neurological significance, yet the most commonly seen in human premature infants.…”

Hypomyelination, memory impairment, and blood–brain barrier permeability in a model of sleep apnea

“…Furthermore, this is the first study to evaluate the blood-brain permeability in a murine model of sleep apnea. Cai et al (2012) reported hypomyelination in a mice model of infantile sleep apnea. They found a reduction in proportion of myelinated fibers in the external capsule, striatum, fornix, and cerebellum.…”

Obstructive Sleep Apnea and Kidney Disease: A Potential Bidirectional Relationship?

“…[125][126][127] The epidemiological and cohort studies linking sleep apnea to kidney disease led Sun and colleagues to examine the effects of sleep apnea on renal function and morphology in a mouse model of intermittent hypoxia. 127 Animals were randomly assigned to either intermittent hypoxia or control groups and primary measures were collected after 3 days, and later at 1, 2, and 8 weeks.…”