Genetic and Environmental Determinants of Neocortical Development: Clinical Applications

Abstract

This chapter reviews the conceptual and methodological tools that permit us to analyze the influences of genetic, epigenetic and environmental determinants on developing neural tissue, including developing neocortex, during early life. During the period of preparation of the neural germinative epithelium, environmental influences, including nutritional, circulatory, maternal and placental factors, can interfere with the genetic program in a very complex way. Whole postimplantation mouse embryo cultures are a powerful tool for the study of environmental, nutritional, hypoxic and genetic factors at this developmental phase. At this step we review particularly the role of recently recognized growth and neurotrophic factors [such as vasointestinal peptide (VIP)] on brain growth, an avenue to explore microcephaly and intrauterine growth retardation. At the step of neuronal migration, we review mainly the alcohol and cocaine-induced disturbances of corticogenesis. Alcohol and cocaine interfere with the development of the human fetal brain. The teratogenic mechanisms of these drugs on neurogenesis were recently explored in animal models. Cocaine severely disturbs neocortical architecture, disrupting horizontal and vertical lamination and inducing an abnormal array of the axonal-dendritic bundles. Cocaine also alters several steps of gliogenesis. The severity of malformations is variable but is evident in all animals exposed to doses comparable to the doses by human cocaine abusers. The cocaine-induced cortical pattern seems to be the result of dyschronologic mitoses and of a defect of the radial glial cells. This pattern may represent the pathological basis of the neuropsychological modifications described in in utero cocaine-exposed children. Immediate early genes (IEGs; c-fos, c-jun, and zif-268) are disturbed by cocaine during development. As transcription factors. IEGs can directly dysregulate target genes. Ethanol locally enhances cell death in the primitive neuroepithelium. During neuronal migration, ethanol induces a premature transformation of the radial glial guides into astrocytes. Ethanol also inhibits late gliogenesis. The resulting postmigratory neocortex displays an abnormal neuronal pattern almost completely deprived of vertical columnization. These glial-neuronal disturbances can explain neuropathological and clinical features of the fetal alcohol syndrome. At the end of and after neuronal migration, the infragranular layers are a sensitive target for perfusion failures/ hypoxias around mid-gestation. During the second half of pregnancy, the transformation of radial glial cells into astrocytic precursors is a target for environtmental disturbances, among which nutritional factors and hypoxial/ischemia are candidates. Several residual neuronal migrations or displacements occurring after mid-gestation have complex pathophysiological relationships with ischemia/hypoxia and with circulatory events. The late germinative zone produces migrating astrocytic precursorsfor the upper neocortex. If confirms the dual origin of astocytic precursors and suggest the transitory existence of a late astroglial pro-tomap destined to upper cortex, which could explain cortical consequences of periventricular leucomalacias (PVLs) and intraventricular hemorrhages (IVHs).