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PubMed2005

Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia.

BACKGROUND: Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission has been implicated in schizophrenia. We studied whether transient inhibition of NMDA receptor activity during early postnatal development would produce a behavioral phenotype resembling that of individuals who are susceptible to develop schizophrenia. METHODS: Rat pups were given injections of the NMDA channel blocker MK801 on postnatal days 7 through 10. This period is akin to the prenatal second trimester of primate development. Cognitive function was tested in adulthood. RESULTS: Treatment with MK801 impaired cognitive flexibility and working memory. The impairment in cognitive flexibility was due to increased perseverative behavior. Treatment did not affect locomotor activity or recognition memory. CONCLUSIONS: These results suggest that a brief disruption of NMDA receptors during a sensitive period of cortical development is sufficient to produce selective cognitive deficits that are relevant to schizophrenia.

Age Factors↗
PubMed1989

Brain plasticity after corpus callosum transection in the newborn rat.

The importance of afferent fibers in the final shaping of the central nervous system has been well established in several papers. In order to study how much one can influence cortical development by changing afferent input to the cortex cerebri, we transected corpus callosum in rats at 2 or 3 postnatal days. Equal numbers of lesioned and control animals were transcardially perfused with mixed aldehydes at postnatal day 6 (P-6) or P-14. Brain tissue was processed for Golgi impregnation, Nissl stain, and quantitative electron microscopic analysis. Morphometric image analysis (MOP 3) of the primary sensory area did not show significant differences with respect to cortical depth and total and apical dendritic length. The cross-sectional area and maximal diameter of neuronal cell bodies were smaller in P-14-lesioned animals. Ultrastructural analysis of the cortex revealed that synaptic density was not reduced in lesioned animals. In conclusion, early in development, rat brain can compensate for major changes in the commissural afferent system.

Animals↗
PubMed2003

Automated detection of gray matter malformations using optimized voxel-based morphometry: a systematic approach.

Malformations of cortical development (MCD) are a recognized cause of epilepsy. Their special significance lies in the fact that, once detected and delineated, they are amenable to surgical removal. However, diagnosis from high-resolution MRI is still difficult, time-consuming, and highly dependent on individual expertise. We have recently proposed a simple procedure to detect cortical dysplasias, using automated procedures available within SPM99 (Wellcome Department, University College London, UK). Here, we aimed to systematically determine the best combination of processing parameters, using an optimized voxel-based morphometry approach. We included 20 patients with a known MCD and compared them to a normal database of 53 healthy, age- and gender-matched controls. The approaches taken during spatial normalization and a number of other parameters were systematically altered in order to find the best combination of parameters. Overall, 99 different approaches were evaluated in different ways. As far as possible, automatic processing and evaluation steps were used. With the number of candidate regions for MCD limited to five per patient, the best approaches resulted in the correct identification of up to 16 of 20 malformations. However, a number of approaches failed to perform well. The reasons for these failures and the implications this has for other studies are discussed. We conclude that voxel-based morphometry is able to detect cortical malformations with a high degree of accuracy. However, specific problems seem to arise when using an optimized protocol for voxel-based morphometry, indicating that this protocol may not be optimal for all voxel-based studies on brain morphology. Our approach, involving systematic alterations of parameters and evaluation, may be useful for other studies.

Adolescent↗
PubMed1992

Astrocytes in cat visual cortex studied by GFAP and S-100 immunocytochemistry during postnatal development.

A monoclonal antibody to glial fibrillary acidic protein (GFAP) and a polyclonal antiserum to the S-100 protein were used to study the expression of these astrocytic proteins in the postnatal visual cortex of the cat. Three changes in antigen expression of these astroglial markers could be distinguished over development. First, the density of cells in the white matter, which are heavily labelled with both antibodies from birth until adulthood, diminishes after the third postnatal weeks. By intracellular filling with Lucifer Yellow the reduction of the cell density can be attributed to the disappearance of large astrocytes with a morphology of transforming radial glia, present only in early postnatal development. Second, heavily labelled, large cells present in the grey matter at the seventh postnatal day have disappeared by the fifth postnatal week. On the basis of their morphology these cells can also be classified as radial glial cells. Finally, astroglial cells of the adult-like stellate form appear to be labelled in the cortical layers between the third and seventh postnatal weeks. While the density of these cells and the S-100 immunoreactivity of the cell bodies is adult-like at the fourth postnatal week, there is a gradual increase of the staining intensity with the GFAP antibody up to the seventh postnatal week. This developmental period is paralleled by the appearance of S-100-positive astrocytic processes. The gradual expression of GFAP immunoreactivity and the increased expression of S-100 is interpreted as reflecting the time course of astrocytic maturation. A possible relation of the maturation of astrocytes and cortical development, both of which are prominent in the time period between the third and seventh postnatal week, is discussed.

Aging↗
PubMed1999

Neutralizing TGF-beta1 antibody infusion in neonatal rat delays in vivo glomerular capillary formation 1.

BACKGROUND: The interruption of transforming growth factor-beta (TGF-beta) signaling with dominant negative type II TGF-beta receptors in bovine glomerular endothelial cells abrogates capillary morphogenesis in vitro, and genetic defects in the TGF-beta1 signaling cascade in mice and humans result in abnormalities of blood vessel morphology. This study sought to determine whether TGF-beta1 participates in renal glomerular capillary development in vivo. METHODS: To inhibit TGF-beta1 action, neutralizing anti-TGF-beta1 IgG was infused intra-arterially into the suprarenal aorta of three-day-old rats, and the glomerular endothelial cell appearance was evaluated two days later by immunohistochemical detection of the endothelium-specific von Willebrand factor, in situ analysis of vascular endothelial growth factor receptor binding, and morphometric study of developing glomerular structures by transmission electron microscopy. RESULTS: The infusion of neutralizing the TGF-beta1 antibody markedly reduced the invasion of comma- and S-shaped bodies by endothelial cells, and inhibited organization of endothelial cells into capillaries in these structures. In addition, capillary lumen formation and endothelial cell fenestration in developing cortical, but not in deep, already mature glomeruli were inhibited by neutralizing TGF-beta1 antibody. Seven days after TGF-beta1 antibody infusion, glomeruli appeared normal, and no reduction in glomerular number was observed. CONCLUSIONS: These findings suggest that TGF-beta1 plays a critical role in the formation of glomerular capillaries during renal development in the rat, and that flattening and fenestration of glomerular capillaries require the action of TGF-beta1.

Animals↗
PubMed1997

Clonal dispersion and evidence for asymmetric cell division in ferret cortex.

Cell lineage analysis with retroviral libraries suggests that clonal progeny disperse widely in rodent cortex. To determine whether widespread dispersion is a general mammalian plan and to investigate phylogenetic differences in cortical development, we analyzed cell lineage in the ferret, a carnivore and near relative of the cat. The ferret possesses a highly developed, folded cerebral cortex, characteristic of higher mammalian species. Progenitor cells of the ferret cerebral cortex were tagged with an amphotropic retroviral library encoding alkaline phosphatase, and sibling relationships were determined using the polymerase chain reaction. Neuronal clones were single neurons (52%) or large clones (48%; average, 7 neurons) containing neurons and glia in widespread cortical locations. Neuronal clones in the ferret labeled at middle to late neurogenesis (embryonic day 33-35) contained large numbers of neurons and showed little tendency to cluster. The large proportion of single neuron clones, contrasted with the large size of multicell clones, suggests that some progenitors divide asymmetrically, producing a postmitotic neuron and regenerating a multipotential cell.

Alkaline Phosphatase↗
PubMed1994

Neurotrophin 3 potentiates neuronal activity and inhibits gamma-aminobutyratergic synaptic transmission in cortical neurons.

Neurotrophins have traditionally been regarded as slowly acting signals essential for neuronal survival and differentiation. However, brain-derived neurotrophic factor and neurotrophin 3 (NT-3) have recently been reported to exert an acute potentiation of synaptic activity at the amphibian neuromuscular junction. Little is known about the role of neurotrophins on functional synapses in the central nervous system. Here we show that NT-3 rapidly increased the frequency of spontaneous action potentials, and it synchronized excitatory synaptic activities in developing cortical neurons. Moreover, the inhibitory synaptic transmission mediated by gamma-aminobutyric acid (GABA) subtype A receptors was found to be reduced by NT-3. Thus, the excitatory effects of NT-3 on spontaneous action potentials were attributable to a reduction of GABAergic transmission. Our findings, together with previous reports of rapid regulation of central nervous system neurotrophin expression by neuronal activity and of the role of GABAergic transmission in cortical plasticity, suggest a mechanism for modulation of synaptic transmission and activity-dependent synaptic modulation in cortical neurons.

Amphibians↗
PubMed1986

Prenatal developmental disturbances in the limbic allocortex in schizophrenics.

Sixty-four autopsied brains of schizophrenic patients were neuropathologically examined and compared with 10 brains of non-schizophrenic controls. Clinical diagnoses were established retrospectively according to the Research Diagnostic Criteria and the International Classification of Diseases. We found: brains without deviations of the sulcogyral pattern of the temporal lobe or abnormal gross configuration (n = 22); brains with abnormal sulcogyral pattern of the temporal lobe or abnormal gross configuration (n = 42): with definite cytoarchitectonic abnormalities of the rostral entorhinal region in the parahippocampal gyrus and, in 16 cases only, in the ventral insular cortex (n = 20); with equivocal changes of the cytoarchitecture in these two regions (n = 22). Generally, these anatomical abnormalities were asymmetric. The histological findings in the two limbic regions consisted mainly of poorly developed structure in the upper layers, with a heterotopic displacement of single groups of nerve cells in the entorhinal region. Particularly, the disturbed structure of the second layer Pre-alpha in medial and central fields of the entorhinal region, situated in the parahippocampal gyrus (group 2a), suggests a disturbance of neuronal migration in a later phase of cortical development.

Adult↗
PubMed2004

GABAA receptors reorganize when layer 4 in ferret somatosensory cortex is disrupted by methylazoxymethanol (MAM).

We established a model of cortical development that arrests the birth of layer 4 cells by injecting methylazoxymethanol (MAM) on embryonic day 33 (E33) in ferrets. This leads to adult somatosensory cortex with a very thin layer 4. Earlier, we determined the relative absence of layer 4 changed the growth and differentiation of the somatosensory cortex and the growth of thalamic afferents into the cortical plate. To identify other features of cortical organization that might be altered after MAM treatment, we assessed the distribution of selected excitatory and inhibitory receptors in area 3b of ferret somatosensory cortex. Initial screening revealed the distribution of several excitatory receptors (NMDA, AMPA, kainate) in E33 MAM-treated cortex was similar to that in normal adult animals. In contrast, the binding pattern of inhibitory GABAA receptors was altered in MAM-treated cortex. Normally, GABAA receptors densely locate in central layers of cortex. In E33 MAM-treated animals, GABAA receptor binding extended superficially, covering a broader area of cortex. Further experiments using antibodies directed against GABAAalpha receptors disclosed that pan alpha GABAA receptors strongly localize to layer 4 in normal area 3b. In E33 MAM-treated cortex, however, GABAAalpha receptors extend outside and are located above and below the very thin layer 4. The redistribution of inhibitory receptors suggests that layer 4 plays an important role in regulating thalamic terminations and also in the resulting ability to refine processing of incoming stimuli.

Animals↗
PubMed1997

Interactions between glial progenitors and blood vessels during early postnatal corticogenesis: blood vessel contact represents an early stage of astrocyte differentiation.

The post-neurogenic period in the mammalian neocortex is characterized by the growth of astrocyte and oligodendrocyte populations and their incorporation into the network of the developing central nervous system (CNS). Many of these glial cells originate as progenitors in the subventricular zone (SVZ) and then migrate into white and gray matter before differentiating. What determines the specific cellular fate of progenitors in vivo is not known, however. In examining the early stages of gliogenesis from progenitors in the SVZ, we noted that interactions with cortical blood vessels took place at what appeared to be an early stage of glial differentiation. We have examined in more detail the interactions of progenitors with blood vessels in the early postnatal rat neocortex after labeling progenitors in vivo with a LacZ-encoding retrovirus. These early interactions are accompanied by an increase in intermediate filament expression, consistent with astrocytic differentiation. Because astrocytes interact with blood vessels and pia, we suggest that such contact represents an early stage in astrocytic differentiation. Furthermore, since angiogenesis and astrogenesis occur over a similar period, the growth of blood vessels may even play a role in the selection of astrocytic fate by a progenitor. As vessel growth slows, fewer progenitors may be directed toward an astrocyte fate, allowing more to differentiate into oligodendrocytes, perhaps explaining the shift from astrocyte genesis to oligodendrocyte genesis during early postnatal cortical development.

Animals↗
PubMed2006

Normal and abnormal fetal brain development during the third trimester as demonstrated by neurosonography.

The multiplanar neurosonographic examination of the fetus enables superb visualization of brain anatomy during pregnancy. The examination may be performed using a transvaginal or a transfundal approach and it is indicated in patients at high risk for CNS anomalies or in those with a suspicious finding during a routine examination. The purpose of this paper is to present a description of the normal brain and of abnormal findings usually diagnosed late in pregnancy, including malformations of cortical development, infratentorial anomalies, and prenatal insults.

Brain↗
PubMed1992

Role of the cytoskeleton during early development.

Oocytes, eggs, and embryos from a diverse array of species have evolved cytoskeletal specializations which allow them to meet the needs of early embryogenesis. While each species studied possesses one or more specializations which are unique, several cytoskeletal features are widely conserved across different animal phyla. These features include highly-developed cortical cytoskeletal domains associated with developmental information, microtubule-mediated pronuclear transport, and rapid intracellular signal-regulated control of cytoskeletal organization.

Animals↗
PubMed1999

Synaptic responses of neurons in heterotopic gray matter in an animal model of cortical dysgenesis.

Neuronal heterotopia is a malformation of cortical development that is closely associated with epilepsy in humans. Despite emerging interest in the structure and function of the heterotopic cortex, little is known about the membrane properties and synaptic connections of these displaced neurons. We used whole-cell patch-clamp and extracellular field potential recordings from heterotopic neurons in slices from young adult rats with experimentally induced cortical dysgenesis to determine if local synaptic connections were present in nodular heterotopia. Complex synaptic responses were observed after electrical stimulation of adjacent white matter. The results suggest that neurons in nodular heterotopic gray matter can form local excitatory and inhibitory synaptic connections and may participate in epileptiform events.

Animals↗
PubMed2005

Presenilins in the developing, adult, and aging cerebral cortex.

Mutations in presenilins are the major cause of familial Alzheimer disease. The involvement of presenilins in the pathogenesis of Alzheimer disease, therefore, has been the subject of intense investigation during the past decade. Genetic analysis of phenotypes associated with presenilin mutations in invertebrate and vertebrate systems has greatly advanced our understanding of the in vivo functions of presenilins. In this review, the authors will summarize the current understanding of presenilin function, with an emphasis on the mammalian cerebral cortex. During development, presenilins play crucial roles in the maintenance of neural progenitor cell proliferation, the temporal control of neuronal differentiation, the survival of Cajal-Retzius neurons, and proper neuronal migration in the developing cerebral cortex. Analysis of presenilin function in the adult cerebral cortex has revealed essential roles for presenilins in synaptic plasticity, long-term memory, and neuronal survival. The authors will also discuss the molecular mechanisms through which presenilins may mediate these functions, including the Notch, CREB, and NMDA receptor-mediated signaling pathways. These diverse functions of presenilins in cortical development and function and neuronal survival have important implications for the pathogenesis of neurodegenerative dementia.

Aging↗
PubMed1998

Developmental expression of human angiotensinogen in transgenic mice.

Transgenic mice containing the human angiotensinogen (HAGT) gene were utilized to determine the developmental regulation of HAGT expression. RNase protection assay on total RNA obtained from whole transgenic fetuses revealed that HAGT expression was first detected at embryonic day 8.5 (E8.5) and was abundant from E9.5 onward. The earliest expression of the HAGT transgene appeared to precede the earliest expression of the endogenous mouse AGT gene by 1-2 days. Northern blot analysis revealed moderate levels of HAGT mRNA in liver and kidney and low levels of HAGT mRNA in heart and brain from E16.5 (day 16.5 of gestation) onward. HAGT mRNA in liver, although abundant during late gestation and in 2-wk-old and adult mice, decreased transiently around birth. In situ hybridization performed on sections from whole fetuses revealed that HAGT mRNA was restricted to the developing liver and heart between E9.5 and E11.5 but became more widespread to include the developing aorta, brain, subcutaneous tissues, and vertebra at E13.5. In situ hybridization analysis on fetal kidneys from late gestation, newborn, and 2-wk-old mice demonstrated a progressive restriction of HAGT mRNA to developing cortical proximal tubular cells. These data illustrate the developmental tissue-specific regulation of HAGT expression and demonstrate that sequences present in the transgene can confer an appropriate developmental expression profile.

Angiotensinogen↗
PubMed2004

[Contribution of MRI to the exploration of partial refractory epilepsy].

The development of MRI has modified clinical practices for patients with epilepsy. MRI examinations are highly contributive to the detection of structural brain abnormalities, and have a major impact on the management of patients with epilepsy. In addition to its major diagnostic role, MRI may help to assess prognosis in patients with refractory partial epilepsy. Structural abnormalities such as hippocampal sclerosis or malformations of cortical development are associated with medically refractory epilepsy. Furthermore, finding a focal lesion on MRI is a good prognostic factor in refractory patients who are candidates for surgery. The sensitivity of MRI to detect small brain lesions is currently excellent, but may be further improved by the use of high-resolution imaging, and new techniques such as quantitative methods or statistical parametric mapping (SPM). In the future, new emerging MR techniques will undoubtedly greatly contribute to improved presurgical management of patients with refractory partial epilepsy.

Anticonvulsants↗
PubMed2003

Evidence for a second wave of oligodendrogenesis in the postnatal cerebral cortex of the mouse.

The existing view is that cortical oligodendrocytes (OLs) in rodents are born from the cortical subventricular zone (SVZ) after birth, but recent data suggest that many forebrain oligodendrocyte progenitor cells (OPCs) are specified much earlier (between E9.5 and E13.5 in the mouse) in the ventricular zone of the ventral forebrain under the control of sonic hedgehog (Shh) and migrate into the cortex afterward. We examined expression of specific early OL markers (PDGFRalpha, PLP/DM20, Olig2, and NG2) in the developing forebrain to clarify this issue. We propose that OPCs colonize the developing cortex in two temporally distinct waves. The gray matter is at least partially populated by a first wave of OPCs that arises in the medial ganglionic eminence and the entopeduncular area and spreads into the cortex via the developing cortical plate. The cerebral cortex benefits from the second wave of OPCs coming from residential SVZ. In the second wave, there might be two different types of precursor cells: PLP/DM20(+) cells populating only inner layers and PDGFRalpha(+) cells, which might eventually myelinate the outer regions as well.

Animals↗
PubMed2005

Segmentation of focal cortical dysplasia lesions using a feature-based level set.

Focal cortical dysplasia (FCD), a malformation of cortical development, is an important cause of medically intractable epilepsy. FCD lesions are difficult to distinguish from non-lesional cortex and their delineation on MRI is a challenging task. This paper presents a method to segment FCD lesions on T1-weighted MRI, based on a 3D deformable model, implemented using the level set framework. The deformable model is driven by three MRI features: cortical thickness, relative intensity and gradient. These features correspond to the visual characteristics of FCD and allow to differentiate lesions from normal tissues. The proposed method was tested on 18 patients with FCD and its performance was quantitatively evaluated by comparison with the manual tracings of two trained raters. The validation showed that the similarity between the level set segmentation and the manual labels is similar to the agreement between the two human raters. This new approach may become a useful tool for the presurgical evaluation of patients with intractable epilepsy.

Adult↗