Miloš Judaš

Extraordinary neoteny of synaptic spines in the human prefrontal cortex

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 two- to 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.

The development of the subplate and thalamocortical connections in the human foetal brain

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.

Chapter 9 Neuronal development in human prefrontal cortex in prenatal and postnatal stages

Publisher Summary The mammalian cerebral cortex is organized in a complex way. Important histogenetic processes that lead to its formation are the proliferation, migration, and differentiation of neurons and glial cells, the growth of afferent and efferent fibers, synaptogenesis, and the elimination of certain cells and axonal collaterals. This chapter discusses the neuronal development in human prefrontal cortex in prenatal and postnatal stages. The neurons destined for the primate cerebral cortex originate prenatally in the germinal zones of the fetal telencephalic wall. The prenatal, perinatal, and postnatal dendritic and axonal (neuronal) development in the human PFC (prefrontal cortex) is traced through six different periods on the basis of data on changes in cortical histogenetic events. Period one represents the onset of dendritic differentiation of pyramidal neurons in the cortical plate (CP). Period two denotes late fetal or preterm infant period. Period three represents postnatal year––neonatal period and infancy. Period four is the second postnatal year, known as “early childhood period.” Period five is the period of childhood and adolescence, whereas period six represents the period of adult morphology.

Correlation between the sequential ingrowth of afferents and transient patterns of cortical lamination in preterm infants

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. The major afferent fibers (thalamocortical, basal forebrain, and corticocortical) grow through the transient “waiting” subplate zone (SP) compartment and accumulate below the cortical plate (CP) between 22 and 26 W. These afferent fibers gradually penetrate the CP after 26 W. The prolonged process of dissolution of the SP can be explained by prolonged growth and maturation of associative connections in the human cerebral cortex. The neurons and circuitry elements of the transient layers are the substrate for transient functional and behavioral patterns. The predominance of deep synapses and deep dendritic maturation underlies the immaturity and different polarity of the cortical electrical response in the preterm infant. The significant changes in the transient SP, together with profound changes in the transient architecture of the neocortical plate, parallel the changes observed in recent MRI studies. The role of the SP in the formation of cortical connections and functions is an important factor in considering the pathogenesis of cognitive deficits after brain lesions in the preterm infant. Anat Rec 267:1–6, 2002.

Prolonged coexistence of transient and permanent circuitry elements in the developing cerebral cortex of fetuses and preterm infants.

The aim of this paper is to evaluate correlative magnetic resonance imaging (MRI) and histological parameters of development of cortical afferents during pathfinding and target selection in transient fetal cerebral laminas in human fetuses and preterm infants. The transient fetal subplate zone, situated between the fetal white matter (i.e. intermediate zone) and the cortical plate, is the crucial laminar compartment for development of thalamocortical and corticocortical afferents. The prolonged coexistence of transient (endogenously active) and permanent (sensorydriven) circuitry within the transient fetal zones is a salient feature of the fetal and preterm cortex; this transient circuitry is the substrate of cerebral functions in preterm infants. Another transient aspect of organization of developing fibre pathways is the abundance of extracellular matrix and guidance molecules in periventricular crossroads of projection and corticocortical pathways. Both the subplate zone and periventricular crossroads are visible on MRI in vivo and in vitro. Hypoxic‐ischaemic lesions of periventricular crossroads are the substrate for motor, sensory, and cognitive deficits after focal periventricular leukomalacia (PVL). Lesions of distal portions of the white matter and the subplate zone are the substrate for diffuse PVL. The neuronal elements in transient fetal zones form a developmental potential for plasticity after perinatal cerebral lesions.

Ontogenesis of goal-directed behavior: anatomo-functional considerations

Recent neuroanatomical and neurophysiological studies in man have revealed ontogenetic events which coincide with broadly defined phases of behavioral and cognitive development. During the early fetal period, early produced neurons make initial synapses which form the basis for the earliest electrical activity of the human brain. The overall immaturity of neuronal connections, in particularly in cortical areas, correlates with the absence of any behavioral pattern or goal-directed movements. In the late fetus and preterm infant, transient accumulation of major afferent pathways, the presence of transient layers (subplate zone) and transient pattern of transmitter-related organization form the neurological basis of cortical electric responses as well as transient behavioral states and sleep patterns. Parallel to the profound structural and chemical reorganization of the human cerebrum during the first 6 postnatal months there is a disappearance of transient behavioral and motor patterns. The previously close spatio-temporal correlation between these events becomes progressively looser. The overproduction of circuitry elements during the subsequent period peaks in associative cortex between 1 and 2 years of age, corresponding to the emergence of skilled actions and cognitive functions. After the elimination of some circuitry elements after the second year of life, the prolonged maturation of goal-directed behavior and the protracted emergence of different cognitive functions correlates with the development plateau of synapse production which can be seen up to 16 years of age. Parallel to the prolonged maturation of postsynaptic elements, there are well defined maturational changes in the chemical properties of associative pyramidal neurons of cortical layer III. These findings correspond to the prolonged maturation of movement-related brain macropotentials as well as other cognition-related potentials, where the last prominent changes were seen after 10 years of age. Although the coincidence of the developmental events does not necessarily mean a causal relationship, the combination of structural and physiological data opens new vistas for the further investigation of the neurobiological basis of goal-directed movement and cognitive behavior.

Species-Dependent Posttranscriptional Regulation of NOS1 by FMRP in the Developing Cerebral Cortex

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 translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is widely expressed, NOS1 protein is transiently coexpressed with FMRP during early synaptogenesis in layer- and region-specific pyramidal neurons. These include midfetal layer 5 subcortically projecting neurons arranged into alternating columns in the prospective Brocas 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 posttranscriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.

Selective Depletion of Molecularly Defined Cortical Interneurons in Human Holoprosencephaly with Severe Striatal Hypoplasia

Cortical excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons follow substantially different developmental programs. In rodents, projection neurons originate from progenitors within the dorsal forebrain, whereas interneurons arise from progenitors in the ventral forebrain. In contrast, it has been proposed that in humans, the majority of cortical interneurons arise from progenitors within the dorsal forebrain, suggesting that their origin and migration is complex and evolutionarily divergent. However, whether molecularly defined human cortical interneuron subtypes originate from distinct progenitors, including those in the ventral forebrain, remains unknown. Furthermore, abnormalities in cortical interneurons have been linked to human disorders, yet no distinct cell population selective loss has been reported. Here we show that cortical interneurons expressing nitric oxide synthase 1, neuropeptide Y, and somatostatin, are either absent or substantially reduced in fetal and infant cases of human holoprosencephaly (HPE) with severe ventral forebrain hypoplasia. Notably, another interneuron subtype normally abundant from the early fetal period, marked by calretinin expression, and different subtypes of projection neuron were present in the cortex of control and HPE brains. These findings have important implications for the understanding of neuronal pathogenesis underlying the clinical manifestations associated with HPE and the developmental origins of human cortical interneuron diversity.

Transient patterns of cortical lamination during prenatal life: do they have implications for treatment?

Transient laminae containing circuitry elements (synapses, postsynaptic neurons and presynaptic axons) appear in the cerebral wall from the eighth postconceptional week (PCW) and disappear with the resolution of the subplate zone after the sixth postnatal month. The first endogeneous synaptic circuitry develops in two laminae, above and below the cortical plate. Mid- and late fetal period (15-23PCW) shows lamination pattern with a thick subplate zone containing GABAergic, glutamatergic and peptidergic neurons, synapses and thalamocortical afferents which are waiting and accumulating in the superficial subplate zone between 21 and 23PCW and these mark regional boundaries. In preterm infants, some thalamocortical fibers relocate to the cortical plate in visual, somatosensory, auditory and associative cortices, forming a framework for sensory-driven connectivity, while other remain engaged in the endogeneous subplate zone circuitry. Corticocortical pathways continue to grow. In the neonatal period, there is a major reorganization of callosal projections and development of short corticocortical connections, dendritic spines and synapses. In conclusion, transient neuronal circuitry underlies transient functions during the fetal, perinatal and early postnatal life and determines developmental plasticity of the cerebral cortex and moderates effects of lesion of the developing brain.

Structural basis of the developmental plasticity in the human cerebral cortex: the role of the transient subplate zone.

We correlated neuroanatomical developmental parameters with sequential ultrasonography scans to reveal the structural basis of functional recovery after early focal hypoxic lesions of the human frontal lobe in premature infants. We studied the transient fetal subplate zone in the premotor and prefrontal cortex in premature, newborn, infant, and young adult brains by acetylcholinesterase (AChE) histochemical, Golgi, and immunocytochemical methods. The structuralin vivo rearrangements of the cerebral wall after perinatal lesions were studied on serial real-time sector scans (5-MHz transducer). The subplate zone contains “waiting” axons and randomly oriented fetal neurons, its developmental peak is between 22 and 34 weeks of gestation, and it is present in the frontal cortex of newborns and disappears after the sixth postnatal month, but individual subplate-like neurons remain until adulthood. Ultrasonography revealed remarkable structural rearrangements of the cerebral wall when the hypoxic lesion occurred during the developmental peak of the subplate zone: anechoic cavities (“cysts”) develop rapidly (within 3 weeks) in premature brains, the rebuilding of these lesions continues after birth, and cavities disappear around the 11th month. We propose that the transient population of “waiting” axons and cells of the subplate zone participate in the structural and functional plasticity of the human cerebral cortex after perinatal brain damage.