Developmental Changes in Oligodendrocyte Genesis, Myelination, and Associated Behavioral Dysfunction in a Rat Model of Intra-generational Protein Malnutrition.

Abstract

Impairments in oligodendrocyte development and resultant myelination deficits appear as a common denominator to all neurological diseases. An optimal in utero environment is obligatory for normal fetal brain development and later life brain functioning. Late embryonic and early postnatal brains from F1 rat born to protein malnourished mothers were studied through a combination of immunocytochemical and quantitative PCR assay for analyzing the relative expression of platelet-derived growth factor receptor-α (PDGFRα), myelin-associated glycoprotein (MAG), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG) to determine oligodendrocyte genesis, differentiation, maturation, and myelination. Myelin integrity and corpus callosum caliber was assessed by Luxol fast blue (LFB) staining, whereas grip strength test and open field activity monitoring for behavioral evaluation in F1 rats. We demonstrate that intra-generational protein deprivation results in drastically low PDGFRα+ oligodendrocyte precursor (OPC) population and significantly reduced expression of myelin protein genes resulting in poor pre-myelinating and mature myelinating oligodendrocyte number, hypo-myelination, and misaligned myelinated fibers. LFB staining and MOG immunolabeling precisely revealed long-term changes in corpus callosum (CC) caliber and demyelination lesions in LP brain supporting the behavioral and cognitive changes at early adolescence and adulthood following maternal protein malnutrition (PMN). Thus, intra-generational PMN negatively affects the oligodendrocyte development and maturation resulting in myelination impairments and associated with behavioral deficits typically mimicking clinical hallmarks of neuropsychiatric disorders. Our results further strengthen and augment the hypothesis "Impaired gliogenesis is a big hit for neuropsychiatric phenotype."