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At least 217 records · Page 12Linked to original sources
PubMed2003

NMDA receptors in cortical development are essential for the generation of coordinated increases in [Ca2+](i) in "neuronal domains".

Spontaneous correlated activity regulates the precision of developing neural circuits. A synchronized elevation of intracellular calcium ion concentration, [Ca(2+)](i), occurred in 5-50 adjacent neurons--known as a "neuronal domain"--in developing neocortex. This coordinated response of neuronal cells is mediated by the diffusion of inositol trisphosphate (IP(3)) via gap-junction channels. In this study, we utilized the N-methyl-D-aspartate (NMDA)-type glutamate receptor epsilon 2 (GluR epsilon 2/NR2B)(-/-) mouse, which does not possess any functional NMDA receptors in the developing neocortex, and showed that NMDA receptors are essential for the generation of "neuronal domains". First, the frequency of spontaneously occurring neuronal domains in brain slices from GluR epsilon 2(-/-) mice was significantly reduced compared to that seen in brain slices from wild-type mice. Secondly, IP(3) injection into a single neuron in a cortical slice from a GluR epsilon 2(-/-) brain resulted in very few neuronal domains being observed, but an injection similarly made into a neuron in a wild-type slice promptly resulted in neuronal domains. Even in the GluR epsilon 2(-/-) brain, the elevation of intracellular [Ca2+](i) was observed frequently in single neurons and microinjection of IP(3) produced an elevation of [Ca2+](i) in the injected cells. These results suggest that the diffusion of IP(3) into the surrounding neurons via gap junctions is almost completely absent in the GluR epsilon 2(-/-) brain. Our results may reflect the critical role of NMDA receptors in the formation of cortical circuitry, probably via the regulation of gap-junction channels between immature cortical neurons.

Animals↗
PubMed2026

A human-specific non-coding RNA for EFHC1, an epilepsy-associated gene, regulates neural stem cell proliferation for cortical development.

Epilepsy is a prevalent brain disorder in humans but rarely occurs naturally in other species, highlighting the potential for human-specific mechanisms in its pathogenesis, and thus, current animal models fail to recapitulate human symptoms. Comparing RNA sequencing (RNA-seq) datasets from human and mouse neural stem cells (NSCs), we identified EFHC1, a juvenile myoclonic epilepsy gene, as exhibiting a human-biased expression. EFHC1 knockdown reduced human NSC proliferation, while its overexpression in mouse embryonic brains increased cortical NSC number. Mechanistically, EFHC1 prevented endoplasmic reticulum stress, thereby reducing inflammatory activation of p38 MAPK and promoting continuous proliferation of human NSCs. We also identified pancEFHC1, a bidirectional promoter-associated non-coding RNA (pancRNA), located at the human EFHC1 promoter. Knockdown of pancEFHC1 in human NSCs increased DNA methylation to reduce EFHC1 expression, with the resulting phenotype rescued by EFHC1 overexpression. We propose that the evolutionary acquisition of pancEFHC1 has introduced a complex regulatory mechanism for EFHC1 expression that allows distinguishing it in humans.

Humans↗
PubMed2006

What is the biological significance of BDNF mRNA targeting in the dendrites? Clues from epilepsy and cortical development.

The neurotrophin brain-derived neurotrophic factor (BDNF) is a regulatory factor of several, partially contrasting, aspects of the biology of neural cells, including survival, growth, differentiation, and cell death. Regulation of the local availability of BDNF at distinct subcellular domains such as the cell soma, dendrites, axons, and spines appears to be the key to conferring spatial and temporal specificity of the different effects elicited by this neurotrophin. This article reviews recent findings in the context of epileptogenesis and visual cortex maturation that showed that different BDNF messenger RNA (mRNA) transcripts are localized at different subcellular locations in hippocampal and cortical neurons. It also reviews findings demonstrating that strong depolarizing stimuli, both in vitro and in vivo, elicit accumulation of BDNF mRNA and protein in the distal dendrites through a signaling pathway involving the activation of the N-methyl-D-aspartate and tyrosine kinase B receptors and an intracellular increase in Ca2+ concentration. Finally, this article proposes that the regulation of the delivery of BDNF mRNA and protein to the different subcellular domains--particularly the dendritic compartment--may represent a fundamental aspect of the processes of cellular and synaptic morphological rearrangements underlying epileptogenesis and postnatal development of the visual cortex.

Animals↗
PubMed1986

Activation of T cell antigen receptor alpha- and beta-chain genes in the thymus: implications for the lineages of developing cortical thymocytes.

Mammalian T lymphocytes mature in the thymus through a series of differentiation events that involve both rapid proliferation and extensive cell death. The mechanisms that govern these processes are currently unknown; however, both mitogenesis and death affect particular subpopulations of cells, suggesting the selective amplification and destruction of specific T cell clones. In mature peripheral T cells, proliferation is most commonly triggered by the recognition of antigen through the T cell antigen receptor complex. If antigen recognition also controls proliferation in the thymus, the differential expression of antigen receptor genes during maturation could play some role in determining the fate of developing T cells. In this study, we examined the expression of the alpha- and beta-chain genes of the T cell antigen receptor in different subpopulations of adult thymocytes. We compared two postmitotic populations--one that appears committed to die and one that appears mature--and several blast cell populations that are enriched for precursors of one or another presumptive lineage. We have found that Lyt-2-, L3T4- precursor thymocytes express much lower levels of both alpha- and beta-chain mRNA than the cells likely to be their immediate descendents. Furthermore, our results show that the cells of the major cortical lineage, which have at least a 95% probability of death, nevertheless express high levels of mature mRNA encoding both the alpha- and the beta-chains of the T cell antigen receptor. These results have important implications for the mechanisms involved in the overproduction and elimination of this major class of T lymphocyte.

Animals↗
PubMed2026

Asparagine Synthetase Deficiency: Neuropathological Evidence of Disrupted Cortical Development.

Asparagine synthetase deficiency (ASNSD) is a rare metabolic disease causing congenital microcephaly, severe developmental delay, and spastic quadriplegia. Although the central nervous system is severely affected, other organ systems appear unaffected by asparagine deficiency. We present an infant homozygous for the mutation c.904-1G>A in the ASNS gene, whose clinical presentation and radiological findings were typical for ASNSD. Following the patient's death at the age of 6 months, histological and immunohistochemical examination of the telencephalon revealed a vast disturbance of migration of neuronal subpopulations, consequently severe disorganization of cortical layers, and thinning of the cerebral cortex. These findings provide novel insights into disease pathogenesis and may explain the hallmark features of ASNSD, including microcephaly and epilepsy.

ASNS gene↗
PubMed1989

Selective elimination of axons extended by developing cortical neurons is dependent on regional locale: experiments utilizing fetal cortical transplants.

In adult rats, cortical neurons that extend an exon through the pyramidal tract (a major subcortical efferent projection of the neocortex) are limited to layer V of about the rostral two-thirds of the neocortex. In neonates, however, pyramidal tract neurons are distributed throughout the neocortex, but all of those found in certain areas, such as the posterior occipital region (including primary visual cortex) selectively lose their pyramidal tract axon (Stanfield et al., 1982) yet maintain axon collaterals to other subcortical targets (O'Leary and Stanfield, 1985). To determine if the regional location of a developing pyramidal tract neuron critically influences the maintenance or elimination of the axon collaterals it initially extends, pieces of cortex from embryonic day 17 (E17) rat fetuses (exposed to 3H-thymidine on E15) were transplanted heterotopically into the cortex of newborn (PO) rats; rostral cortex was placed into the posterior occipital region (R----O), or posterior occipital cortex into a rostral cortical locale (O----R). The retrograde tracers Fast blue (FB) and Diamidino yellow (DY) were used to assay for the presence of specific populations of cortical projection neurons within the autoradiographically identified transplants. In terms of the extension and maintenance of pyramidal tract axons, the transplanted neurons behave like the host neurons of the recipient cortical region rather than like those of their site of origin. At P40, following FB injections into the pyramidal decussation on P34, pyramidal tract neurons are labeled within the O----R transplants, but none can be labeled within R----O transplants, although in the same R----O cases transplanted neurons are labeled by an injection of DY in the superior colliculus. However, at P13 pyramidal tract neurons can be identified within the R----O transplants, as well as in the host occipital cortex, following injections made on P9, a period when the distribution of pyramidal tract neurons in normal rats is widespread (Stanfield and O'Leary, 1985b). In a second series of host rats, on P34 FB was injected in the pyramidal decussation of the O----R cases, or in the superior colliculus of the R----O cases, and in both groups DY was injected into the region of contralateral cortex homotopic for the new location of the transplant. On P40, in both the O----R and R----O transplants, many neurons singly labeled with FB or DY are found, but no double dye-labeled cells are seen.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Cortical development and thalamic pathology in schizophrenia.

In this article, morphological data suggesting that brain development may be altered in schizophrenia are reviewed in relation to the major events in neural development. In the absence of severe defects in brain structure in individuals with schizophrenia, developmental processes governing the establishment, refinement, and maintenance of connections are potential sites of pathological involvement. Alterations in connectional patterns are likely to result in activity-dependent changes in gene expression for molecules involved in the neurotransmission process, with functional consequences. Loss of cells in the thalamus may be primary or secondary to cortical or other subcortical pathology. Loss of thalamic cells and/or of corticothalamic inputs could lead to disintegration of thought processes by a failure in functional brain states dependent on collective oscillation of large ensembles of cortical and thalamic neurons.

Cerebral Cortex↗
PubMed1998

Nonhuman primate model of the effect of prenatal cocaine exposure on cerebral cortical development.

To investigate the effects of prenatal cocaine exposure on the corticogenesis in primates we developed a monkey model in which pregnant animals received 10 mg/kg cocaine orally twice a day from the 40th to the 102nd day of pregnancy. The animals gave birth at term, and brains of the 2-month and 1.5-year-old infants were examined. Examination revealed the structural abnormalities throughout the cerebral cortex that would be expected from modulation of the nonselectively diffusing circulation-derived monoamines. They include: (1) reduction in the number of cortical cells, which most likely reflects abnormal cell proliferation; (2) inappropriate positioning of cortical neurons, which resulted from alterations in migration of cortical cells; and (3) altered glial morphology. The structural alterations were accompanied by abnormalities in animal temperament reminiscent of those seen in human infants of drug-abusing mothers. As predicted by the morphologic studies, we found that cocaine treatment produced significant changes in the levels of monoamines and their receptors in all laminae of the frontal, parietal, temporal, and occipital regions of the fetal cerebral wall. This indicates that cocaine abuse by pregnant human mothers may affect the global levels of monoamines in the fetal brain and, in doing so, interfere with a broad range of developmental events regulated by these chemicals.

Aging↗
PubMed2006

Maturation of cerebral electrical activity and development of cortical folding in young very preterm infants.

OBJECTIVE: The aim of this study was to examine the relationship between cortical development and cerebral electrical activity at early gestational ages. METHODS: We obtained EEGs (7.2+/-3.8 days) and MR brain images (3.2+/-2.9 days) after birth in 17<30 week gestation infants without evidence of focal brain injury The EEGs were assessed for discontinuity and characteristic maturational features (delta brush, occipital and temporal sawtooth); cortical development was quantified from MR scans using a specially designed computer programme to measure cortical folding. RESULTS: The inter-burst interval shortened and cortical folding increased with increasing post-menstrual age (PMA). In contrast, the minimum duration of bursts was independent of PMA and cortical folding. Delta brush (8-20 Hz activities) was seen at all PMAs; temporal and occipital sawtooth activities were always more prominent than delta brush but were seen less frequently with increasing PMA and complexity of cortical folding. CONCLUSION: There was a positive correlation between some but not all maturational features of the preterm neonatal EEG and the complexity of whole brain cortical folding and PMA. These relationships were strong for the inter-burst interval, a global measure of maturation, but not strongly seen for regional features such as occipital and temporal sawtooth within this gestational age range. SIGNIFICANCE: Combining neurophysiological examination with detailed neuroimaging gives insights into developmental changes occurring in the very preterm brains and suggests further comparative studies focusing on measures of focal brain development at different gestational ages.

Cerebral Cortex↗
PubMed1989

Chronic exposure of developing cortical neurons to GABA down-regulates GABA/benzodiazepine receptors and GABA-gated chloride currents.

Cultures of cerebral neurons were prepared from chick embryos, 8.5 days in ovo, and maintained in vitro. Following chronic exposure of these cells to GABA, the levels of [3H]flunitrazepam binding in situ and electrophysiological responsiveness to gamma-aminobutyric acid (GABA) was examined. Treatment with 100 microM GABA for 7 days reduced [3H]flunitrazepam binding in situ by 70 +/- 8% compared to untreated controls. The binding of [3H]N-methylscopolamine was unaffected by this treatment. The reduction in [3H]flunitrazepam binding was prevented by concomitant exposure of developing neurons to the GABA antagonist R 5135, suggesting that GABAA receptor occupancy is required. The loss of bezodiazepine receptors was dependent on the GABA concentration in the culture medium and a half-saturation (IC50) value of 11.2 +/- 3.7 microM was estimated. Whole-cell patch-clamp recordings were obtained to assess the functional properties of the labile receptor pool observed in the binding studies. Neurons cultured with 100 microM GABA for 7 days showed a 60-70% reduction in the peak current amplitudes observed in response to application of 10-100 microM GABA. However, the rate of rapid desensitization, quantified by measuring changes in input conductance, was unchanged by chronic GABA exposure, yielding decay time constants of 27.1 +/- 2.1 and 34.7 +/- 4.7 s for control and treated cells, respectively. The results are consistent with a GABA modulation of the GABAA/benzodiazepine receptor complex by means of down-regulation.

Animals↗
PubMed2002

Effects of genetic depletion of monoamines on somatosensory cortical development.

Raised levels of serotonin cause alterations in the development of the barrelfield of the primary somatosensory cortex (S1) in rodents. We examined the development of S1 in genetic mouse models in which the levels of serotonin and/or dopamine and noradrenaline are drastically reduced. Mice lacking the vesicular monoamine transporter type 2 (VMAT2 KO) are hypomorphic with rare pups surviving until postnatal day (P) 6. Serotonin, dopamine and noradrenaline are almost undetectable in the brain. In S1 we find that the segregation of thalamocortical axons into whisker patterns is delayed by 1 day and that layer IV granular neurons fail to form normal barrels. Moreover, the growth of cortical layers II-IV is reduced. Despite severe malnutrition, we show that these alterations are not caused by increased cell death in the thalamus or S1. Moreover, the maturation of cortical neurons is not altered as reflected by calcium-binding protein immunolabeling. Mice lacking both VMAT2 and monoamine oxidase type A (MAOA) were generated. VMAT2-MAOA DKO mice are hypomorphic but survive until P13. Increased levels of serotonin but profoundly reduced dopamine and noradrenaline levels are found in the brains. In S1, alterations are similar to those observed in MAOA KO mice: thalamocortical axons and granular neurons failed to form barrels. In addition there is a severe reduction in the thickness of the upper cortical layers as in the VMAT2 KO mice. These results show that monoamines have no instructive effect per se on the formation of thalamocortical patterning in S1. However, monoamines appear to be essential for the normal cytoarchitectonic maturation of the granular (IV) and supragranular cortical layers (II-III). Since developmental cell death and chemoarchitectonic differentiation of these neurons are not modified, it is possible that these alterations result from migration defects and/or from altered synaptic maturation.

Animals↗
PubMed2002

Cajal-Retzius and subplate neurons: their role in cortical development.

Cajal-Retzius (C-R) neurons and their processes form a synaptic network in the marginal zone of the early telencephalon prior to the arrival of the first wave of radial migration of neuroblasts from the subventricular zone. Their origin is not yet proved but may be either the medial ganglionic eminence or the mesencephalic neuromere. These bipolar or multipolar neurons populate the molecular layers of both the fetus and the adult, though sparse in the adult. Their thick axon emits collaterals that make synaptic contact with pyramidal neurons initially in layer 6 and later within all layers. C-R neurons produce GABA, possibly ACh, several calcium-binding proteins (e.g. calmodulin; parvalbumin; possibly calretinin), several neuropeptides and are rich in ribosomes. Subplate neurons, beneath the cortical plate, emit pioneer axons in the incipient formation of the internal capsule and also commissural fibres of the early hippocampus. C-R cells express products of the genes reelin, LIS1 and DS-CAM, that mediate radial neuroblast migration and lamination of the cortical plate and are important in the pathogenesis of lissencephaly. In addition to forming the first intrinsic synaptic circuits of the cortical plate and its first afferent and efferent connections with subcortical structures, they may play additional roles in the formation of ocular dominance columns, in regulating neuronogenesis and in cortical repair. They do not later disappear by apoptosis as we previously thought, but their functional role in the mature brain is unknown.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2003

Pax6 regulates cell adhesion during cortical development.

Pax6 is a member of an evolutionarily conserved family of transcription factors. It is developmentally regulated and is required for the normal embryonic development of the central nervous system, eye and pancreas. Pax6 mutations in the mouse result in the Small eye (Sey) phenotype. Heterozygous mice have eye defects and homozygotes die immediately after birth lacking eyes, nasal cavities and with severe brain abnormalities, including a malformed cerebral cortex. Recent work has established that there are changes in expression of cell adhesion molecules and these may underlie at least a part of the Pax6(Sey/Sey) phenotype. Here we used cell transplants and explant cultures to investigate the role of Pax6 in cell adhesion. Pax6(Sey/Sey) embryonic cortical cells transplanted into wild-type embryonic cortex were observed to segregate from wild-type cells and form dense clusters. Cells migrating from explants of Pax6(Sey/Sey) embryonic cortex clustered to a greater extent than cells migrating from wild-type controls. These new data support the hypothesis that Pax6 exerts a cell-autonomous effect on the adhesiveness of cortical cells.

Animals↗
PubMed1993

Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development.

The distribution of neurons expressing the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d) in the lateral and medial temporal lobes of schizophrenic and matched control brains was investigated in a systematic blind analysis. Schizophrenics had significantly lower numbers of NADPH-d neurons in the hippocampal formation and in the neocortex of the lateral temporal lobe but significantly greater numbers of NADPH-d neurons in the white matter of the lateral temporal lobe and a tendency toward greater numbers in parts of the parahippocampal white matter. The distorted distribution of NADPH-d neurons in the lateral temporal lobe, which may be explained by developmental disturbances, such as impaired neuronal migration or an alteration in the death cycle of transitory subcortical neurons, is similar to that found in the prefrontal cortex of schizophrenics. Alterations of cortical ontogenesis, as reflected in the distribution of NADPH-d neurons, appear to be widespread among neocortical association fields in schizophrenics and may provide a clue to the cause of the disease.

Aged↗
PubMed1989

Effect of environmental enrichment during nutritional rehabilitation on body growth, blood parameters and cerebral cortical development of rats.

Environmental enrichment has been reported to aid recovery from behavioral deficits associated with malnutrition in infants and young rats. This study investigated whether corresponding neuroanatomical changes could be detected. Rats were suckled either by well-fed dams or dams malnourished during lactation. At weaning, well-fed males were either housed in pairs (standard condition, SC) or 12 per large cage with toys (enriched condition, EC) and fed a 17% protein diet (SC control and EC control, respectively). Malnourished pups were fed either a 17% (rehabilitation; "rehab") or a 6% (low protein) protein diet and housed in the SC or EC environment (SC rehab, EC rehab, SC low protein, and EC low protein). After 30 d there were no differences in hematocrit, serum total protein and albumin levels between SC and EC animals. Rehab rats had significantly lower serum total protein and albumin levels than did controls. Cortical thickness and dendritic branching of occipital cortex pyramidal cells were evaluated. Early malnutrition did not permanently affect cortical thickness. EC rehab rats had thicker cortices than did SC rehab rats at almost all locations measured. SC rehab rats had fewer high order dendrites than did SC controls. The difference in dendritic branching between EC and SC rats was 44% among rehab rats, 21% among controls and 11% (not significant) among low protein-fed rats. Environmental enrichment during nutritional rehabilitation enhances dendritic branching and thickness of the occipital cortex.

Animals↗
PubMed1989

Protein fatty acid acylation in developing cortical neurons.

Neuron-enriched cultures derived from embryonic day 17 rat cerebral cortex were incubated in the presence of [3H]myristic or [3H]palmitic acid. Analysis of radiolabeled proteins by two-dimensional gel electrophoresis and fluorography revealed extensive incorporation of fatty acids into a small number of neuronal proteins. The major acylated proteins had apparent molecular weights and isoelectric points as follows: 87,000, 4.3; 63,000, 4.4; 45,000, 4.4; and 20,000, 5.3. After labeling with [3H]myristic acid, the radioactivity associated with these proteins was identified as myristic acid, which was attached via an ester linkage. All four of the major acylated neuronal proteins were found to be membrane-bound and enriched in growth cones. By virtue of its molecular weight, isoelectric point, subcellular distribution, and peptide map, the 87-kilodalton polypeptide was shown to be equivalent to pp80, a phosphoprotein that has been described in developing and mature synaptic terminals. The 45-kilodalton acylated protein also appears to coincide with another growth cone phosphoprotein, pp40. Acylation may serve as a mechanism to regulate the function of these proteins, or may play a role in directing them to the nerve terminal membrane.

Acylation↗
PubMed2006

Methylisothiazolinone, a neurotoxic biocide, disrupts the association of SRC family tyrosine kinases with focal adhesion kinase in developing cortical neurons.

Methylisothiazolinone (MIT) is a biocide widely used in industrial and cosmetic products with potential as a neurotoxicant. We previously reported that short acute exposures to relatively high concentrations of MIT (100 microM) lead to widespread and selective neuronal death in vitro. To evaluate the biological properties of chronic exposures to MIT, freshly dissociated rat cortical neurons were continuously exposed to low concentrations (0.1-3 microM) of the biocide in serum-containing media. Although we observed minimal effects on cell viability, MIT induced a dramatic inhibition of neurite outgrowth. Immunoblotting and immunoprecipitation experiments revealed that focal adhesion kinase (FAK) phosphorylation was primarily affected by the MIT treatment. The phosphorylation level at tyrosines 576 and 861 of FAK was significantly decreased and likely contributed to the overall reduction of tyrosine phosphorylation of this protein. MIT inhibited Src family kinases (SFKs) in cell-free assays and led to the physical dissociation of FAK from the signaling complexes that it normally forms with c-Src and Fyn in developing neurons. High-density neuronal cultures were then employed to increase cell-to-cell contact. This approach resulted in an overall enhancement of SFKs and FAK phosphorylation and could overcome the deficits induced by MIT. This study suggests that a disruption of FAK-SFK complexes due to SFK inhibition leads to FAK dysfunction, with detrimental effects to immature neurons. Prolonged exposure to low levels of MIT and related compounds may have damaging consequences to the developing nervous system.

Animals↗
PubMed2002

Neurotrophins and cortical development.

The mammalian cerebral cortex requires the proper formation of exquisitely precise circuits to function correctly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. Although the development of the cerebral cortex has been well described anatomically, the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections are just beginning to be understood. Moreover, despite evidence that coordinated patterns of activity underlie reorganization of brain circuits during critical periods of development, the molecular signals that translate activity into structural and functional changes in connections remain unknown. Recently, the neurotrophins have emerged as attractive candidates not only for regulating neuronal differentiation in the developing brain, but also for mediating activity-dependent synaptic plasticity. The neurotrophins meet many of the criteria required for molecular signals involved in neuronal differentiation and plasticity. They are present in the cerebral cortex during development and their expression is regulated by synaptic activity. In turn, the neurotrophins themselves strongly influence both short-term synaptic plasticity and long-term potentiation and depression. In addition to their functional effects, the neurotrophins also profoundly regulate the structural changes that underlie axonal and dendritic differentiation. Finally, the neurotrophins have been implicated in mediating synaptic competition required for activity-dependent plasticity during the critical period. This chapter presents and discusses the rapidly accumulating evidence that the neurotrophins are critical for neuronal differentiation and that they may be involved in activity-dependent synaptic refinement in the developing cerebral cortex.

Animals↗