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PubMed2000

Cortical development and saccade planning: the ontogeny of the spike potential.

The spike potential is a sharply timed positivity which precedes eye movements in adults, and is thought to indicate cortical planning of saccades. While the spike potential is observed under most conditions in adults, it has not been reported in young infants. In the present study we shed light on the ontogeny of the spike potential by demonstrating for the first time its existence in a group of older infants (12 months). This result is consistent with a relatively delayed onset of cortical control over saccades during development.

Age Factors↗
PubMed1983

Toxic effect of phenytoin on developing cortical neurons in culture.

Studies were undertaken to determine the effect of chronic phenytoin exposure on developing neurons. Cerebral cortex from 16-day fetal mice was utilized to prepare primary dissociated cell cultures. Phenytoin was added to the cultures 10 days after plating and the cultures were harvested on day 17. Cortical cultures were assayed for neuronal cell number by phase microscopy and for high-affinity uptake of 3H-labeled gamma-aminobutyric acid (GABA) by both radioautography and scintillation spectrometry. Neuronal cell counts demonstrated a highly significant decrement in the number of neurons in cultures exposed to phenytoin at 15, 25, and 50 micrograms/ml. 3H-GABA-labeled neurons constituted 13% of the neurons present in both control and phenytoin-exposed cultures. These data indicate that phenytoin is toxic to cortical neurons in culture and that GABAergic neurons are affected to the same extent as the total neuronal population.

Animals↗
PubMed2002

Identification of calcium-dependent and -independent signaling pathways involved in polychlorinated biphenyl-induced cyclic AMP-responsive element-binding protein phosphorylation in developing cortical neurons.

Cyclic AMP (cAMP)-responsive element-binding protein (CREB) is a transcription factor important in developing nervous system cells and is activated by a variety of signaling molecules. Aroclor 1254 (A1254), a polychlorinated biphenyl mixture, perturbs Ca(2+) homeostasis and increases CREB phosphorylation in rat neonatal cortical cell cultures in a time- and concentration-dependent manner. The present experiments determined that the cell type responding to A1254 with Ca(2+) increases and phosphorylated CREB (phospho-CREB) was predominantly of neuronal morphology and microtubule-associated protein (MAP2)-positive phenotype. Similarly, glutamate (100 microM) increased phospho-CREB immunoreactivity selectively in MAP2-immunopositive cells. Using Western blotting and immunocytochemical techniques, we identified key signal transduction pathways operative in phosphorylating CREB in cortical cell cultures and examined their participation in 3 ppm A1254-induced CREB activation. Cortical cultures treated with glutamate, forskolin or the phorbol ester phorbol 12-myristate 13-acetate exhibited robust increases in phospho-CREB. Tetrodotoxin (1 microM) completely inhibited CREB phosphorylation by A1254, suggesting that synaptic activity is involved in A1254-induced CREB activation. Buffering [Ca(2+)](i) with bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester in the absence of extracellular Ca(2+) partially inhibited A1254-induced CREB phosphorylation. Inhibition of mitogen-activated protein kinase (10 microM U0126) or protein kinase C (PKC; bisindoylmaleimide, 5 microM) activation did not inhibit A1254-induced CREB phosphorylation. By contrast, inhibition of protein kinase A (PKA) with 100 microM PKA inhibitor peptide, PKI, blocked A1254-induced CREB phosphorylation. Thus, we examined whether A1254 activates PKA by increasing cAMP; 10 microM forskolin, but not A1254, elevated intracellular cAMP levels. These results indicate that in neocortical cells in culture, CREB phosphorylation occurs via Ca(2+)-, PKA-, and PKC-dependent pathways. Furthermore, A1254-induced CREB phosphorylation occurs predominantly in neurons, is dependent on synaptic activity and mediated by Ca(2+)- and PKA-dependent pathways.

Animals↗
PubMed2003

Multiple dose-dependent effects of Lis1 on cerebral cortical development.

Humans with heterozygous inactivating mutations of the Lis1 gene display type I lissencephaly, a severe form of cortical dysplasia hypothesized to result from abnormal neuronal migration. Previously we reported the construction of an allelic series of the Lis1 gene in mice to analyze the effects of graded reduction of LIS1 protein on the pathogenesis of this disorder and demonstrated a cell autonomous defect in neuronal migration (Hirotsune et al., 1998). Here we report the systematic examination of the consequences of dosage reduction of LIS1 on neocortical development using wild-type, null heterozygous (45% LIS1 protein), and compound null/hypomorphic (35% LIS1 protein) mice. The development of the preplate, Cajal-Retzius cells, and the radial glial scaffold appeared unaffected by LIS1 levels. However, a dose-dependent morphologic change in disorganization of the subplate was noted. LIS1 dose-dependent defects in neuronal migration were found in vivo and in vitro. The position and number of mitotic cells in the ventricular zone were more abnormal as LIS1 levels decreased, suggesting defects in interkinetic nuclear migration and neuroblast proliferation. LIS1 dose-dependent progressive thinning of the cortex and ventricular zone occurred by programmed cell death. Thus, in addition to its requirement for cell autonomous neuronal migration, LIS1 influences the generation and survival of cortical ventricular zone neuroblasts. These studies reveal the importance of LIS1 levels in orderly cerebral cortical morphogenesis and suggest new insights into the pathogenesis of type I lissencephaly.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2002

Emx2: a gene responsible for cortical development, regionalization and area specification.

Mouse Emx2 homeobox gene is a very good dorsal marker for the developing cerebral cortex, as it is mainly expressed in this area from the very beginning of corticogenesis. Its cortical expression includes proliferating neuroblasts of the neuroepithelium, or ventricular zone, and the postmitotic Cajal-Retzius cells, known to control neuronal radial migration. Analysis of the phenotype of Emx2 null embryos has shown that this transcription factor plays important roles in neuroblast proliferation, migration and differentiation, as well as in the development of the diencephalon, where it has been shown to cooperate with Otx2. Moreover, the graded distribution of EMX2 homeoprotein along the antero-posterior and medial-lateral cortical axis, is responsible for the patterning of the forebrain, in particular for the specification process that defines cortical territories and area identity during neocortical development. Emx2 participates to this process as Pax6 and COUP-TF1. Finally Emx2 is very interesting from the evolutionary point of view, as it has been shown to share a high degree of homology in its sequence and function with Vax1, another homeobox gene regulating basal forebrain development. This homology traces back to Emx and Vax gene families, which are strongly related, as they are thought to derive from a common ancestor gene.

Animals↗
PubMedDate not supplied

[Acetylcholinesterase activity during the cortical development of the cat brain].

Acetylcholinesterase (AChe) hydrolyses acetylcholine to choline and acetate, thereby inactivating the neurotransmitter. However, the possible non-cholinergic function of this enzyme has been recently suggested. In the present work, changes in AChe activity during the postnatal development of the cat brain are described, in order to show if the enzyme could play a part in the maturing processes of the CNS. The study was performed in the frontal and parietal cortices, area 17 and areas 18 and 19 as a whole in the 15 and 30 days postnatal stages. Significant increases with age were observed in all the brain areas under study. It is suggested that this enzyme activity play a part in the maturation of the cat brain cortices, possibly in the cholinergic development and/or as a cell growth regulatory factor.

Acetylcholinesterase↗
PubMed2005

Architecture and mineralization of developing cortical and trabecular bone of the mandible.

Ossification of the presumptive trabecular bone in the mandibular condyle and the presumptive cortical bone in the mandibular corpus of the pig mandible was investigated during development, using micro-computed tomography (microCT). Three-dimensional architecture and mineralization characteristics were assessed from ten pigs of different developmental ages. In the condyle, increases in trabecular thickness and separation and a decrease in the trabecular number, led to an unchanged bone volume fraction. A conversion from rod-like into plate-like trabeculae was observed. Bone volume and trabecular thickness were always higher in the corpus, where an increase in bone volume fraction was caused by an increase in the trabecular thickness and a decrease in separation. A transition from a plate-like structure into a more compact structure took place. The average degree of mineralization in the condyle and the corpus increased with age. In the corpus, the degrees of mineralization were higher than in the condyle. The differences between the condyle and corpus and the changes with age could be explained by differences in the distribution of mineralization within the trabecular elements. Generally, the degrees of mineralization increased from the surface toward the centers of the trabecular elements, indicating growth of the trabecular elements by the surface apposition of new mineral.

Animals↗
PubMed2006

An RNA gene expressed during cortical development evolved rapidly in humans.

The developmental and evolutionary mechanisms behind the emergence of human-specific brain features remain largely unknown. However, the recent ability to compare our genome to that of our closest relative, the chimpanzee, provides new avenues to link genetic and phenotypic changes in the evolution of the human brain. We devised a ranking of regions in the human genome that show significant evolutionary acceleration. Here we report that the most dramatic of these 'human accelerated regions', HAR1, is part of a novel RNA gene (HAR1F) that is expressed specifically in Cajal-Retzius neurons in the developing human neocortex from 7 to 19 gestational weeks, a crucial period for cortical neuron specification and migration. HAR1F is co-expressed with reelin, a product of Cajal-Retzius neurons that is of fundamental importance in specifying the six-layer structure of the human cortex. HAR1 and the other human accelerated regions provide new candidates in the search for uniquely human biology.

Aging↗
PubMed2004

alpha3beta1 integrin modulates neuronal migration and placement during early stages of cerebral cortical development.

We show that alpha3 integrin mutation disrupts distinct aspects of neuronal migration and placement in the cerebral cortex. The preplate develops normally in alpha3 integrin mutant mice. However, time lapse imaging of migrating neurons in embryonic cortical slices indicates retarded radial and tangential migration of neurons, but not ventricular zone-directed migration. Examination of the actin cytoskeleton of alpha3 integrin mutant cortical cells reveals aberrant actin cytoskeletal dynamics at the leading edges. Deficits are also evident in the ability of developing neurons to probe their cellular environment with filopodial and lamellipodial activity. Calbindin or calretinin positive upper layer neurons as well as the deep layer neurons of alpha3 integrin mutant mice expressing EGFP were misplaced. These results suggest that alpha3beta1 integrin deficiency impairs distinct patterns of neuronal migration and placement through dysregulated actin dynamics and defective ability to search and respond to migration modulating cues in the developing cortex.

Actins↗
PubMed2006

Human disorders of cortical development: from past to present.

Epilepsy and mental retardation, originally of unknown cause, are now known to result from many defects including cortical malformations, neuronal circuitry disorders and perturbations of neuronal communication and synapse function. Genetic approaches in combination with MRI and related imaging techniques continually allow a re-evaluation and better classification of these disorders. Here we review our current understanding of some of the primary defects involved, with insight from recent molecular biology advances, the study of mouse models and the results of neuropathology analyses. Through these studies the molecular determinants involved in the control of neuron number, neuronal migration, generation of cortical laminations and convolutions, integrity of the basement membrane at the pial surface, and the establishment of neuronal circuitry are being elucidated. We have attempted to integrate these results with the available data concerning, in particular, human brain development, and to emphasize the limitations in some cases of extrapolating from rodent models. Taking such species differences into account is clearly critical for understanding the pathophysiological mechanisms associated with these disorders.

Animals↗
PubMed2005

Expression of alpha5 nicotinic acetylcholine receptor subunit mRNA during hippocampal and cortical development.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated pentameric cation channels of alpha and beta subunits. The alpha5 subunit, when added to heteromeric complexes, alters pharmacological and physiological properties of nAChRs, which may be important during development. Here we have evaluated the pre- and postnatal expression of alpha5 subunit mRNA in rat cortex and hippocampus using highly sensitive in situ hybridization. In the cortex, alpha5 mRNA was detected in the subplate, claustrum, and endopiriform nucleus at embryonic day 18 (E18), areas with sustained expression into adulthood. Transient cortical expression was detected in numerous cells, scattered mainly in layers V and II/III, during the first 2 postnatal weeks. In the hippocampus, alpha5 transcripts first appeared in the CA1 region at E18. During postnatal development, increased hybridization signal was detected in CA1 and CA3 pyramidal neurons and granule cells of the dentate gyrus, which strongly contrasted with the low levels in the adult. Interneurons in CA1/CA3 stratum radiatum and moleculare, and in the hilus region of the dentate gyrus, strongly expressed alpha5 mRNA in postnatal and adult animals. With double in situ hybridization, co-expression of alpha5 and alpha7 mRNAs was detected in a subpopulation of hippocampal interneurons. In contrast, in the subiculum, numerous cells exhibited strong hybridization signal for alpha5 and alpha7 mRNAs, but co-expression was rarely detected. In conclusion, similar to other nAChR subunits, there is transient expression of alpha5 mRNA during cortical and hippocampal development. This expression pattern places nicotinic receptors containing the alpha5 subunit in a position to regulate glutamatergic and GABAergic transmission during the postnatal period.

Animals↗
PubMedDate not supplied

The role of serotonin in early cortical development.

The cerebral cortex is widely innervated by serotonin (5-HT)-containing axons originating from neurons in the raphe nuclei. The early development of this monoamine system in the cortex prompted speculation long ago that it has important functions in cortical maturation and plasticity. Here we review evidence, derived from a plethora of studies and from our recent unpublished work, that supports an important role for 5-HT in a number of major events in the developing cortex, especially at the early stages. This evidence points to a regulatory role for 5-HT in neuronal proliferation, migration and differentiation, and in preventing apoptotic cell death.

Animals↗
PubMed2003

Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptor-associated PDZ proteins in developing cortical neurons.

Postsynaptic molecules with PDZ domains (PDZ proteins) interact with various glutamate receptors and regulate their subcellular trafficking and stability. In rat neocortical development, the protein expression of AMPA-type glutamate receptor GluR1 lagged behind its mRNA expression and rather paralleled an increase in PDZ protein levels. One of the neurotrophins, brain-derived neurotrophic factor (BDNF), appeared to contribute to this process, regulating the PDZ protein expression. In neocortical cultures, BDNF treatment upregulated SAP97, GRIP1, and Pick1 PDZ proteins. Conversely, BDNF gene targeting downregulated these same PDZ molecules. The BDNF-triggered increases in PDZ proteins resulted in the elevation of their total association with the AMPA receptors GluR1 and GluR2/3, which led to the increase in AMPA receptor proteins. When Sindbis viruses carrying GluR1 or GluR2 C-terminal decoys disrupted their interactions, GluR2 C-terminal decoys inhibited both BDNF-triggered GluR1 and GluR2/3 increases, whereas GluR1 C-terminal decoys blocked only the BDNF-triggered GluR1 increase. In agreement, coexpression of SAP97 and GluR1 in nonneuronal HEK293 cells increased both proteins compared with their single transfection, implying mutual stabilization. This work reveals a novel function of BDNF in postsynaptic development by regulating the PDZ protein expression.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Birthdate and cell marker analysis of scrambler: a novel mutation affecting cortical development with a reeler-like phenotype.

The reeler mutation in mice produces an especially well characterized disorder, with systematically abnormal migration of cerebral cortical neurons. The reeler gene encodes a large protein, termed Reelin, that in the cortex is synthesized and secreted exclusively in the Cajal-Retzius neurons of the cortical marginal zone (D'Arcangelo et al., 1995). In reeler mutant mice, loss of Reelin protein is associated with a systematic loss of the normal, "inside-out" sequence of neurogenesis in the cortex: neurons are formed in the normal sequence but become localized in the cortex in a somewhat inverted, although relatively disorganized "outside-in" pattern. Here we show that the scrambler mutant mouse exhibits a loss of lamination in the cortex and hippocampus that is indistinguishable from that seen in the reeler mouse. We use BrdU birthdating studies to show that scrambler cortex shows a somewhat inverted "outside-in" sequence of birthdates for cortical neurons that is similar to that previously described in reeler cortex. Finally, we perform staining with the CR-50 monoclonal antibody (Ogawa et al., 1995), which recognizes the Reelin protein (D'Arcangelo et al., 1997). We show that Reelin immunoreactivity is present in the scrambler cortex in a normal pattern, suggesting that Reelin is synthesized and released normally. Our data suggest that scrambler is a mutation in the same gene pathway as the reeler gene (Relnrl) and is most likely downstream of Relnrl.

Animals↗
PubMed2001

Cell migration and cerebral cortical development.

This annotation describes the clinical and pathological features of several conditions believed to result from a primary defect in cell migration which include the lissencephalies, pachygria, polymicrogyrias, and focal cortical dysplasia. A variety of factors must be considered in pathogeneses, including cellular proliferation, cell death, post-migrational intracortical growth and development, axonogenesis and dendritogenesis. At least two distinct types of lissencephaly exist. Classic (also known as Type I) lissencephaly is the prototypic pattern being seen in autosomal dominant Miller-Dieker syndrome, in addition to autosomal recessive and X-linked forms. The Miller-Dieker syndrome locus (LIS-1) encodes the platelet activating factor acetylhydrolase-1, beta1 subunit. The gene for an X-linked form of lissencephaly (XLIS) encodes a protein called doublecortin. Cobblestone (type II) lissencephaly is most commonly seen in patients with the Walker-Warburg syndrome, and also occurs in a group of disorders associated with congenital muscular dystrophy, including Finnish 'muscle-eye-brain' disease and Fukuyama muscular dystrophy. Controversy exits as to whether polymicrogyria is a malformation or a disruption of development. The answer is likely both. Polymicrogyria is believed to arise from defects occurring between 17 and 25 or 26 weeks gestation. Heterotopia can be sporadic, inherited as a simple Mendelian trait, or may be part of a more complex syndrome being characterized by collections of disorganized grey matter in inappropriate places. X-linked periventricular heterotopia syndrome is caused by mutations in filamin-1. In addition to those described above, many other syndromes show lissencephaly, pachygyria and polymicrogyria and many cases are not easily classified into any particular syndrome.

Brain Diseases↗
PubMed2006

A fuzzy system for helping medical diagnosis of malformations of cortical development.

Malformations of the cerebral cortex are recognized as a common cause of developmental delay, neurological deficits, mental retardation and epilepsy. Currently, the diagnosis of cerebral cortical malformations is based on a subjective interpretation of neuroimaging characteristics of the cerebral gray matter and underlying white matter. There is no automated system for aiding the observer in making the diagnosis of a cortical malformation. In this paper a fuzzy rule-based system is proposed as a solution for this problem. The system collects the available expert knowledge about cortical malformations and assists the medical observer in arriving at a correct diagnosis. Moreover, the system allows the study of the influence of the various factors that take part in the decision. The evaluation of the system has been carried out by comparing the automated diagnostic algorithm with known case examples of various malformations due to abnormal cortical organization. An exhaustive evaluation of the system by comparison with published cases and a ROC analysis is presented in the paper.

Algorithms↗
PubMed2001

Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization.

Lissencephaly is a severe brain malformation in humans. To study the function of the gene mutated in lissencephaly (LIS1), we deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimics a mutation described in one lissencephaly patient with a milder phenotype. Homozygotes are early lethal, although heterozygotes are viable and fertile. Most strikingly, the morphology of cortical neurons and radial glia is aberrant in the developing cortex, and the neurons migrate more slowly. This is the first demonstration, to our knowledge, of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalomocortical innervation are also abnormal. Biochemically, the mutant protein is not capable of dimerization, and enzymatic activity is elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of PAF-AH. This mutation allows us to determine a hierarchy of functions that are sensitive to LIS1 dosage, thus promoting our understanding of the role of LIS1 in the developing cortex.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1997

Focal transmantle dysplasia: a specific malformation of cortical development.

We report 18 patients who presented prior to age 20 years with epilepsy or fixed neurologic deficits. MRI showed signal abnormality extending from the cortex to the superolateral wall of the lateral ventricle. Histology showed cortical disorganization, neuronal cytomegaly, balloon cells, indistinct cortical gray matter-white matter junctions, and variable accompanying astrogliosis. We propose that this transmantle dysplasia is a specific anomaly resulting from abnormal stem cell development.

Adolescent↗