The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by twoto threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders.association cortex | critical period | schizophrenia | synaptogenesis

The developing human cerebrum displays age-specific changes in its patterns of lamination. Among these, the subplate zone is the most prominent transient compartment because growing major afferent systems temporarily reside in this zone, establish synapses and take part in cellular interactions that are crucial for subsequent cortical development. We explored the potential of magnetic resonance imaging (MRI) for tracing the developmental history of the most prominent cortical layer (the subplate zone) and other laminar compartments of the fetal cerebral wall between 15 and 36 weeks post-ovulation. We found that changes in the MRI lamination pattern of the human fetal cerebral wall are predominantly caused by changes in the subplate zone. Histochemical staining of the extracellular matrix (ECM) enables selective visualization of the subplate zone and correlation with an increase in MRI signal intensity in the subplate zone and ingrowth and accumulation of thalamocortical and corticocortical afferents and their subsequent relocation to the cortical plate. Thus, dynamic changes in the MRI appearance of the subplate zone and histochemical staining of its ECM can be used as indirect parameters for an assessment of normal versus disturbed unfolding of crucial histogenetic events that are involved in prenatal shaping of the human cerebral cortex.

The aim of this review is to present clinically relevant data on prenatal development of thalamocortical connections in the human brain. The analysis is based on extensive Zagreb Neuroembryological Collection, including more than 500 prenatal human brains stained with various classical neurohistological, as well as modern histochemical and immunohistochemical methods. The connection of thalamocortical axons during the 'waiting' period with transient cortical subplate zone and subsequent synaptic engagement in the cortical plate is the main connectivity event in the late foetus and preterm infant. This connectivity is the structural substrate for the endogeneous subplate and sensory-driven circuitry generating transient electrical phenomena and may represent a transient network in the developmental history of consciousness.

The postnatal development and lifespan alterations in basal dendrites of large layer IIIC and layer V pyramidal neurons were quantitatively studied. Both classes of neurons were characterized by rapid dendritic growth during the first postnatal months. At birth, layer V pyramidal neurons had larger and more complex dendritic trees than those of layer IIIC; however, at 1 postnatal month both classes of neurons displayed a similar extent of dendritic outgrowth. In addition, after a more than year-long "dormant" period of only fine dendritic rearrangement, layer IIIC pyramidal neurons displayed a second period of dendritic growth, starting at the end of the second year and continuing in the third year. During that period, the dendritic tree of layer IIIC pyramidal neurons became more extensive than that of layer V pyramidal neurons. Thus, layer IIIC pyramidal neurons appear to show a biphasic pattern of postnatal dendritic development. Furthermore, the childhood period was characterized by transient increase in size of pyramidal cell somata, which was more pronounced for neurons in layer IIIC. These structural changes occurred during both the period of rapid cognitive development in preschool children and the period of protracted cognitive maturation during the childhood, puberty, and adolescence.

We analyzed the developmental history of the subplate and related cellular compartments of the prenatal and early postnatal human cerebrum by combining postmortem histological analysis with in vivo MRI. Histological analysis was performed on 21 postmortem brains (age range: 26 postconceptional weeks to 6.5 years) using Nissl staining, AChE-histochemistry, PAS-Alcian blue histochemistry, Gallyas' silver impregnation, and immunocytochemistry for MAP2, synaptophysin, neurofilament, chondroitin sulfate, fibronectin, and myelin basic protein. The histological findings were correlated with in vivo MRI findings obtained in 30 age-matched fetuses, infants, and children. We analyzed developmental reorganization of major cellular (cell bodies, growing axons) and extracellular (extracellular matrix) components of the subplate and the developing cortex/white matter interface. We found that perinatal and postnatal reorganization of these tissue components is protracted (extending into the second year of life) and characterized by well-delineated, transient and previously undescribed structural and molecular changes at the cortex/white matter interface. The findings of this study are clinically relevant because they may inform and guide a proper interpretation of highly dynamic and hitherto puzzling changes of cortical thickness and cortical/white matter interface as described in current in vivo MRI studies.

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Transient patterns of regional, laminar, modular, neuronal, and functional organization are essential features of the developing cerebral cortex in preterm infants. Analysis of cytological, histological, histochemical, functional, and behavioral parameters revealed that transient cerebral patterns develop and change rapidly between 24 weeks post ovulation (W) and birth. Key words: subplate zone; thalamocortical system; acetylcholinesterase; associative connectionsThe prenatal development of the cerebral cortex is characterized by transient patterns of regional, laminar, modular, and neuronal organization (Kostović, 1990a). Whereas the transient patterns of the laminar organization and neuronal circuitry elements have been well documented in both classical (His, 1904; Boulder Committee, 1970) and more recent (Marin-Padilla, 1988;Kostović, 1990a;Rakic, 1995) literature, the majority of recent studies have focused on the transient patterns of the regional and areal organization involved in the processes of early areal specification and genetic control of cortical development (Rubenstein and Rakic, 1999).

SUMMARY Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, results from loss of function of the RNA-binding protein FMRP. Here we show that FMRP regulates the translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is ubiquitously expressed, NOS1 protein is transiently co-expressed with FMRP during early synaptogenesis in layer- and region-specific subpopulations of pyramidal neurons. These include mid-fetal layer 5 subcortically projecting neurons arranged into alternating columns in the prospective Broca’s area and orofacial motor cortex. Human NOS1 translation is activated by FMRP via interactions with coding region binding motifs absent from mouse Nos1 mRNA, which is expressed in mouse pyramidal neurons, but not efficiently translated. Correspondingly, neocortical NOS1 protein levels are severely reduced in developing human FXS cases but not FMRP-deficient mice. Thus, alterations in FMRP post-transcriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.