Axonal development in the cerebral white matter of the human fetus and infant

Abstract

After completion of neuronal migration to form the cerebral cortex, axons undergo rapid elongation to their intra- and subcortical targets, from midgestation through infancy. We define axonal development in the human parietal white matter in this critical period. Immunocytochemistry and Western blot analysis were performed on 46 normative cases from 20-183 postconceptional (PC) weeks. Anti-SMI 312, a pan-marker of neurofilaments, stained axons as early as 23 weeks. Anti-SMI 32, a marker for nonphosphorylated neurofilament high molecular weight (NFH), primarily stained neuronal cell bodies (cortical, subcortical, and Cajal-Retzius). Anti-SMI 31, which stains phosphorylated NFH, was used as a marker of axonal maturity, and showed relatively low levels of staining (approximately one-fourth of adult levels) from 24-34 PC weeks. GAP-43, a marker of axonal growth and elongation, showed high levels of expression in the white matter from 21-64 PC weeks and lower, adult-like levels beyond 17 postnatal months. The onset of myelination, as seen by myelin basic protein expression, was approximately 54 weeks, with progression to "adult-like" staining by 72-92 PC weeks. This study provides major insight into axonal maturation during a critical period of growth, over an age range not previously examined and one coinciding with the peak period of periventricular leukomalacia (PVL), the major disorder underlying cerebral palsy in premature infants. These data suggest that immature axons are susceptible to damage in PVL and that the timing of axonal maturation must be considered toward establishing its pathology relative to the oligodendrocyte/myelin/axonal unit.

Impact of daily high-dose caffeine exposure on developing white matter of the immature ovine brain

“…Importantly, the ovine model allowed us to assess the effects of caffeine at a stage of brain development that is similar to that of the very preterm human infant with respect to the major periods of gliogenesis (18,19), axonal development (20), and myelination (18). Our findings suggest that daily high-dose caffeine treatment does not cause structural alterations or injury in the developing cerebral WM or GM.…”

Neurocognitive and Academic Outcomes at Age 10 Years of Extremely Preterm Newborns

“…35 For example, very preterm newborns are less able than infants closer to term to synthesize growth factors in the amounts needed for normal development. 36 Brain developmental processes underway at midgestation and after, including neuronal migration, oligogenesis, axonal and synapse formation, and myelination, [37][38][39][40] appear to be especially vulnerable to these growth factor deficiencies. 41 In addition, the reduced quantities of these growth promoters are also suboptimal for protecting against adversity, 42 including a host of potentially harmful exposures before, during, and after delivery, with many differing qualitatively (as well as quantitatively) from those experienced by term infants.…”

Impaired Neurodevelopmental Outcome After Mild Germinal Matrix-Intraventricular Hemorrhage

“…[10][11][12] Indeed, microglial activation in germinal matrix and periventricular white matter has been shown in postmortem human premature brain with GMH-IVH. 9,13 A related possibility for a deleterious effect involves free radical-mediated effects on differentiating oligodendrocytes, and perhaps also rapidly growing axons in cerebral white matter, 14 related in part to release of nonheme iron from the hemorrhage and by the activation of microglia, as in the neurobiology of periventricular leukomalacia. 15 However, it is noteworthy that the only significant deleterious anatomic effect of mild GMH-IVH detected by MRI studies at term equivalent age involved cortical and deep gray matter development.…”