Synapses develop concurrently and at identical rates in different layers of the visual, somatosensory, motor, and prefrontal areas of the primate cerebral cortex. This isochronic course of synaptogenesis in anatomically and functionally diverse regions indicates that the entire cerebral cortex develops as a whole and that the establishment of cell-to-cell communication in this structure may be orchestrated by a single genetic or humoral signal. This is in contrast to the traditional view of hierarchical development of the cortical regions and provides new insight into the maturation of cortical functions.

Oligodendrocytes are cells that myelinate axons, providing saltatory conduction of action potentials and proper function of the central nervous system. Myelination begins prenatally in the human, and the sequence of oligodendrocyte development and the onset of myelination are not thoroughly investigated. This knowledge is important to better understand human diseases, such as periventricular leukomalacia, one of the leading causes of motor defi cit in premature babies, and demyelinating disorders such as multiple sclerosis (MS). In this review we discuss the spatial and temporal progression of oligodendrocyte lineage characterized by the expression of specifi c markers and transcription factors in the human fetal brain from the early embryonic period (5 gestational weeks, gw) until midgestation (24 gw). Our in vitro evidence indicated that a subpopulation of human oligodendrocytes may have dorsal origin, from cortical radial glia cells, in addition to their ventral telencephalic origin. Furthermore, we demonstrated that the regulation of myelination in the human fetal brain includes positive and negative regulators. Chemokines, such as CXCL1, abundant in proliferative zones during brain development and in regions of remyelination in adult, are discussed in the view of their potential roles in stimulating oligodendrocyte development. Other signals are inhibitory and may include, but are not limited to, polysialic acid modifi cation of the neural cell adhesion molecule on axons. Overall, important differences in temporal and spatial distribution and regulatory signals for oligodendrocyte differentiation exist between human and rodent brains. Those differences may underlie the unique susceptibility of humans to demyelinating diseases, such as MS.

The cortical subventricular zone (SVZ), a proliferative compartment in the forebrain, has a uniquely important role during the second half of intrauterine development in human. This is best observed in numerous neonatal pathologies that result from prenatal SVZ damage. These conditions highlight a need to better understand the contribution of the SVZ to the development of the human cerebral cortex. With this goal in mind, we analyze histological organization, cell proliferation, and molecular diversity in the human fetal SVZ, from 7 to 27 gestational weeks (gw), using light and electron microscopy, immunohistochemistry, and in vitro methods. Complex histological organization distinguishes human cortical SVZ from that of other mammals. In vitro quantification showed that approximately 50% of cells in the VZ/SVZ region are neurons, 30% are astroglia, 15% are nestin + cells, with other cell types representing smaller fractions. Immunolabeling with BrdU, showed that a considerable number of cells (approximately 10%) are generated in the human cortical SVZ during midgestation (18-24gw), in in vitro conditions. Immunofluorescence with cell type specific markers and BrdU revealed that all major cell types, neural precursors (nestin + ), astroglia including radial glia (GFAP + , vimentin + ), and oligodendrocyte progenitors (PDGFR-α + ), were proliferating. An increase in the ratio of the size of the SVZ to VZ, protracted period of cell proliferation, as well as cellular and histological complexity of the human fetal SVZ, are directly related to the evolutionary expansion of the human cerebral cortex.

Schizophrenia is a disease of abnormal brain development. Considerable evidence now indicates that environmental factors have a causative role in schizophrenia. Elevated incidence of the disease has been linked to a wide range of disturbances in the prenatal environment and to social factors and drug intake during adolescence. Here we examine neurodevelopment of the prefrontal cortex in the first trimester of gestation and during adolescence to gain further insight into the neurodevelopmental processes that may be vulnerable in schizophrenia. Early embryonic development of the prefrontal cortex is characterized by cell proliferation, including renewal of progenitor cells, generation of early transient cell populations and neurogenesis of subcortical populations. Animal models show that curtailing early gestational cell proliferation produces schizophrenia-like pathology in the prefrontal cortex and mimics key behavioral and cognitive symptoms of the disease. At the other end of the spectrum, elimination of excitatory synapses is the fundamental process occurring during adolescent maturation in the prefrontal cortex. Adverse social situations that elevate stress increase dopamine stimulation of the mesocortical pathway and may lead to exaggerated synaptic pruning during adolescence. In a non-human primate model, dopamine hyperstimulation has been shown to decrease prefrontal pyramidal cell spine density and to be associated with profound cognitive dysfunction. Development of the prefrontal cortex in its earliest stage in gestation and in its final stage in adolescence represents two critical periods of vulnerability for schizophrenia in which cell proliferation and synaptic elimination, respectively, may be influenced by environmental factors.

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In this study we examine possible origins and migratory routes of human cortical neurons, with special emphasis on the preplate and layer I. In embryonic stages, two main cell types, Cajal-Retzius cells, and cells labeled with interneuron markers (calretinin, calbindin and GABA), were present in the preplate layer. In addition, a number of preplate GABAergic cells co-expressed either Nkx2.1 or Dlx transcription factors, findings consistent with their origin in the ganglionic eminence and subsequent tangential migration to the layer I. The orientation of the leading process indicates that some of these cells descend to the cortical plate. However, the finding of radially oriented GABAergic, NKX2.1 + and DLX + cells in the cortical ventricular zone, argues that, unlike in rodents, a significant subpopulation of these cells originates in the cortical ventricular zone. In embryonic stages, expression of Reelin in Cajal-Retzius cells as well as Reelin/DLX2 + cells in the embryonic ganglionic eminence and the olfactory region, suggest that these cells in human may have diverse origins. In later fetal stages in human (17-22 gestational weeks) layer I and the newly formed subpial granular layer, contained a population of small interneurons that originated mainly in the lateral ganglionic eminence, since the majority of these cells were double-labeled with DLX/GABA, and rarely with NKX2.1/GABA. Therefore, neurons in the human cortical layer I are heterogeneous, with more complex origin and migratory routes than in rodents. In addition to the ganglionic eminence, both the expended subventricular zone and subpial granular layer, contribute to the neuronal population of the developing layer I and underlining cortical plate.

Premature infants exhibit neurodevelopmental delay and reduced growth of the cerebral cortex. However, the underlying mechanisms have remained elusive. Therefore, we hypothesized that neurogenesis in the ventricular and subventricular zones of the cerebral cortex would continue in the third trimester of pregnancy, and that preterm birth would suppress neurogenesis. To test our hypotheses, we evaluated autopsy materials from human fetuses and preterm infants of 16–35 gestational weeks (gw). We noted that both cycling and non-cycling Sox2+ radial glial cells as well as Tbr2+ intermediate progenitors were abundant in human preterm infants until 28 gw. However, their densities consistently decreased from 16 through 28 gw. To determine the effect of premature birth on neurogenesis, we employed a rabbit model and compared preterm (E29, 3 days old) and term pups (E32, <2h age) at an equivalent post-conceptional age. Glutamatergic neurogenesis was suppressed in preterm rabbits, as indicated by reduced number of Tbr2+ intermediate progenitors and increased number of Sox2+ radial glia. Additionally, hypoxia inducible factor-1α, vascular endothelial growth factor, and erythropoietin were higher in term than preterm pups, reflecting the hypoxic intrauterine environment of just-born term pups. Proneural genes, including Pax6, Neurogenin-1 and -2, were higher in preterm rabbit pups compared to term pups. Importantly, neurogenesis and associated factors were restored in preterm pups by treatment with dimethyloxallyl glycine—a hypoxia mimetic agent. Hence, glutamatergic neurogenesis continues in the premature infants, preterm birth suppresses neurogenesis, and hypoxia-mimetic agents might restore neurogenesis, enhance cortical growth, and improve neurodevelopmental outcome of premature infants.