Congenital heart disease (CHD) is among the most common birth defect. Children with CHD frequently display long-term intellectual and behavioral disability. Emerging evidence indicates that cardiac anomalies lead to a reduction in cerebral oxygenation, which appears to profoundly impact the maturation of cerebral regions responsible for higher order cognitive functions. In this Review, we focus on the potential mechanisms by which dysregulation of cortical neuronal development during early life may lead to the significant cognitive impairments that commonly occur in children with CHD. Further understanding of the mechanisms underlying cortical dysmaturation due to CHD is required to identify strategies for neonatal neuroprotection and for mitigating developmental delays in this patient population.

BackgroundThe ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation. Tissue plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS), where it regulates cell fate. In particular, tPA has been reported to protect oligodendrocytes from apoptosis and to facilitate the migration of neurons. Here, we investigated whether tPA can also participate in the migration of OPCs during CNS development and during remyelination after focal white matter lesion.MethodsOPC migration was estimated by immunohistological analysis in spinal cord and corpus callosum during development in mice embryos (E13 to P0) and after white matter lesion induced by the stereotactic injection of lysolecithin in adult mice (1 to 21 days post injection). Migration was compared in these conditions between wild type and tPA knock-out animals. The action of tPA was further investigated in an in vitro chemokinesis assay.ResultsOPC migration along vessels is delayed in tPA knock-out mice during development and during remyelination. tPA enhances OPC migration via an effect dependent on the activation of epidermal growth factor receptor.ConclusionEndogenous tPA facilitates the migration of OPCs during development and during remyelination after white matter lesion by the virtue of its epidermal growth factor-like domain.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0160-5) contains supplementary material, which is available to authorized users.

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