Disturbed myelinogenesis and recovery in hyperphenylalaninemia in rats: An immunohistochemical study

https://doi.org/10.1016/0014-4886(92)90200-AGet rights and content

Abstract

Chronic hyperphenylalaninemia (HPA) in rats has been used as an experimental model of the human inborn error of metabolism phenylketonuria (PKU). Impaired brain development in PKU and HPA is reflected in reduced myelin formation. We have used immunohistochemistry, with antibodies to cell-specific antigenic markers, to investigate the cellular basis of the hypomyelination in the corpus callosum and cerebral cortex of rats made hyperphenylalaninemic from Postnatal Days 3–17. The rats were then allowed to recover until Day 59. No effects were seen on the number and differentiation pattern of ganglioside GD3-expressing glial progenitors. Myelin basic protein and 2′3′-cyclic nucleotide 3′-phosphohydrolase (CNP) immunostaining demonstrated a reduction in myelin formation in the corpus callosum and subcortical white matter at 12 and 17 days postnatal. However, numbers of CNP+ oligodendrocytes appeared normal throughout development. No reactive astrogliosis was seen at any stage. The intensity of axonal neurofilament immunostaining was reduced in the corpus callosum at 17 days. In layers II and III of the cortical gray matter there was an increase in the cell packing density and a concomitant decrease in cell body size. Myelination in the corpus callosum was rapid during the recovery period with no difference noted at Day 59. Axonal neurofilament staining also returned to normal in the corpus callosum. However, recovery became increasingly incomplete away from the corpus callosum into the cortical gray matter. Our data suggest a primary effect of HPA on axonal maturation with hypomyelination consequential upon this.

References (25)

  • R. Curtis et al.

    Development of macroglial cells in rat cerebellum. I. Use of antibodies to follow early in vivo development and migration of oligodendrocytes

    J. Neurocytol.

    (1988)
  • C. Gravel et al.

    Maturation of the corpus callosum of the rat: I. Influence of thyroid hormones on the topography of callosal projections

    J. Comp. Neurol.

    (1990)
  • Cited by (25)

    • Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria

      2016, Molecular Genetics and Metabolism
      Citation Excerpt :

      However, converging evidence from animal and human research suggest that cortical gray matter is also affected in PKU. Studies employing murine models of PKU have found reduced GM thickness [19], nerve cell size [20], synaptic density [21,22], and dendritic arborization [23] in PKU mice/rats compared to wild-type animals. In addition, early histological studies of humans with untreated PKU reported GM effects including stunted dendritic growth [24], decreased dendritic spines [25], reduced nerve cell size [24], and less distinct cortical lamination [24] compared healthy individuals without PKU.

    View all citing articles on Scopus
    View full text