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PubMed2007

Asymmetric ERM activation at the Schwann cell process tip is required in axon-associated motility.

Axon-associated Schwann cell (SC) motility and process dynamics are crucial in the development and regeneration of the peripheral nervous system (PNS). The bipolar morphology of SCs represents an unexplored conundrum in terms of directed motility. Using fluorescence time-lapse microscopy of transfected SCs within myelinating dorsal root ganglion (DRG) explants, we demonstrate cycling of SCs between bipolar and highly motile, unipolar morphologies as a result of asymmetric process retraction and extension. Unipolar SC motility appears nucleotaxic in nature, similar to the movement of neurons on radial glia during cortical development. We also show that asymmetric process retraction is associated with the activation of ERM (ezrin/radixin/moesin) proteins and subsequent recruitment of ezrin-binding phospho-protein 50 kDa (EBP50) at the retracting process tip. This activation occurs in response to localized synthesis of phosphatidylinositol (4,5)-bisphosphate (PIP2) at this site. Finally, we demonstrate that the activation of ERM proteins at the SC process tip is essential for motility and the maintenance of SC polarity, as ERM disruption yields a dysfunctional, multi-polar cell. These results demonstrate that specializations at the tips of SC processes regulate their dynamics, which in turn is associated with directed motility in these cells.

Animals↗
PubMed1998

Cortical malformations: a significant cause of paediatric neurological morbidity.

Disorders of cortical development are a significant cause of epilepsy, developmental delay and congenital neurological deficits in children of all ages. Disruption of neuronal proliferation, differentiation, migration and organization during the middle trimester are recognized as the basis of most of these disorders. With advances in magnetic resonance imaging and increasing recognition of the characteristic radiological appearance of these lesions, a variety of lesions are now described. Furthermore, detailed clinical and genetic studies have lead to the recognition of clinicopathological syndromes of cortical maldevelopment with specific modes of inheritance. Our understanding of these disorders is increasing rapidly and will continue to do so with improvements in neuroimaging, advances in developmental neurobiology and heightened clinician awareness.

Brain↗
PubMed1996

Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology.

One hallmark of tuberous sclerosis (TSC) is the presence of highly epileptogenic dysplastic cerebral cortex (tubers) composed of abnormally shaped neurons and giant cells. Mutation of the TSC gene (TSC2) may disrupt differentiation and maturation of neuronal precursors, since the TSC2 gene product tuberin is believed to regulate cellular proliferation. To test the hypothesis that cells in tubers may retain the molecular phenotype of embryonic or immature neurons, tubers from five TSC patients were probed with antibodies to proteins expressed in neuronal precursors (nestin, Ki-67, and proliferating cell nuclear antigen). Many dysmorphic neurons and giant cells in tubers were stained by these antibodies, while neurons in adjacent normal and control cortex were not labeled. To further characterize the molecular phenotype of cells in tubers, we developed a methodology in which poly(A)+ mRNA was amplified from immunohistochemically labeled single cells in paraffin-embedded brain specimens. This approach enabled us to detect mRNAs encoding nestin, and other cytoskeletal elements, cell cycle markers, and synthetic enzymes present in individual nestin-stained cells by means of reverse Northern blotting. We conclude that the presence of immature phenotypic markers (mRNAs and proteins) within tubers suggests disruption of cell cycle regulation and neuronal maturation in TSC during cortical development. Characterization of multiple mRNAs within fixed, immunohistochemically labeled cells provides a powerful tool for studying gene expression and the molecular pathophysiology of many neurologic diseases.

Biomarkers↗
PubMed2003

Development of action and the clinical continuum.

The development of action is depicted as consisting of changes in the task-specific couplings between perception, movement, and posture. It is argued that this approach may provide a much needed basis from which attempts can be made at theoretically unifying the constituents of the clinical continuum (viz., early detection, diagnosis, prognosis, and intervention). Illustrative examples germane to this approach are given with regard to how posture serves as a constraint on the emergence of reaching movements and how cortical development influences the coordination of leg movements as revealed by a study involving infants with white matter lesions. Particular attention is paid to early detection and it is recommended that further improvements to this aspect of the clinical continuum can be derived from combining serial qualitative and quantitative (kinematic) assessments with brain-imaging techniques. It is emphasized that quantitative assessments should incorporate experimental manipulations of perception, movement or posture during transitional periods in development. Concluding comments include consideration of the timing of early intervention.

Cerebral Cortex↗
PubMed2001

Reelin-immunoreactive neurons in the adult vertebrate pallium.

Reelin, an extracellular matrix protein, plays a crucial role in cortical development. By using Reelin-immunohistochemistry in different vertebrates (fish, amphibians, reptiles, and mammals : insectivores, odontocetes, rodents, carnivores and man) we show here that Reelin is also expressed by a variety of neurons in the adult pallium. In the everted telencephalon of the zebrafish, Reelin-positive neurons are widely distributed over the dorsal pallium. In land vertebrates, the most consistent and evolutionary conserved location of Reelin-expressing neurons is in the cell-sparse molecular layer associated with laminated cortical organization. We describe an additional heterogeneous population of Reelin-positive neurons outside the molecular layer, the location and distribution of which are more variable, and which may reflect major evolutionary changes in cortical architecture. In squamate reptiles, the Reelin-negative main cell layer is flanked by a superficial and a deep plexiform layer which both contain Reelin-expressing neurons. In mammals, Reelin-positive interneurons are dispersed throughout layers II--VI; the human neocortex is particularly poor in Reelin-positive interneurons. Reelin is also expressed by large stellate and modified pyramidal neurons in layer II of the mammalian entorhinal cortex, and in the superficial lateral cortex of lizards. Examination of this cell population (layer II Pre-alpha) in human brains of different age groups points to a decrease in Reelin-expression in the course of adult life.

Amphibians↗
PubMed2002

Ultrastructural features of the acetylcholine innervation in the developing parietal cortex of rat.

To follow on a recent quantitative study of the developing cholinergic (ACh) innervation in rat neocortex, axon varicosities identified by electron microscopic immunocytochemistry with a highly sensitive antibody against choline acetyltransferase (ChAT) were examined in the primary somatosensory area (Par1) of rats at postnatal ages (days) P8, P16, and P32. As visualized and measured in single thin sections, and compared with those of unlabeled varicosities selected at random in the same photomicrographs, the ChAT-immunostained profiles displayed intrinsic and relational features very similar to those previously described in the same cortical area of adult rat (Umbriaco et al. [1994] J. Comp. Neurol. 348:351-373). At the three postnatal ages, the immunoreactive profiles were comparable in shape, size, and vesicular content in all cortical layers, but showed an increasing frequency of mitochondria with age, reaching 44% at P32. Synaptic junctions were observed on 6.3 to 8.7% of these sectional profiles, indicating an average synaptic incidence of 17% for whole varicosities, again comparable to that in the adult (14%). As in adult, the junctions made by the rare synaptic ChAT-immunostained varicosities were always single, usually symmetrical, and more frequently found on dendritic branches than spines. Thus, cortical ACh varicosities displayed intrinsic and relational features similar to adult ones as soon as this innervation was installed, suggesting that a diffuse mode of transmission and ambient level of ACh could play a major role in the diverse effects of this neuromodulator during cortical development.

Acetylcholine↗
PubMed2003

Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis.

Numb and Numblike, conserved homologs of Drosophila Numb, have been implicated in cortical neurogenesis; however, analysis of their involvement in later stages of cortical development has been hampered by early lethality of double mutants in previous studies. Using Emx1(IREScre) to induce more restricted inactivation of Numb in the dorsal forebrain of numblike null mice beginning at E9.5, we have generated viable double mutants that displayed striking brain defects. It was thus possible to examine neurogenesis during the later peak phase (E12.5-E16.5). Loss of Numb and Numblike in dorsal forebrain resulted in neural progenitor hyperproliferation, delayed cell cycle exit, impaired neuronal differentiation, and concomitant defects in cortical morphogenesis. These findings reveal novel and essential function of Numb and Numblike during the peak period of cortical neurogenesis. Further, these double mutant mice provide an unprecedented viable animal model for severe brain malformations due to defects in neural progenitor cells.

Animals↗
PubMed1990

Nerve growth factor receptor immunoreactivity is transiently associated with the subplate neurons of the mammalian cerebral cortex.

Nerve growth factor and its receptor (NGFR) are known to be present in diverse embryonic and neonatal central nervous system tissues, including the cerebral cortex. However, the identity of the cortical cells expressing NGFR immunoreactivity has not been established. We have used immunolabeling coupled with [3H]thymidine autoradiography to identify such cells in ferret and cat brain. Polyclonal antibodies raised against a synthetic peptide corresponding to a conserved amino acid sequence of the NGFR were used for this purpose. Western (immunologic) blot analyses show that these antibodies specifically recognize NGFR and precursor proteins. In both species, NGFR immunoreactivity is primarily associated with the early generated and transient subplate neuron population of the developing neocortex, as indicated by the following evidence: the immunoreactive cells (i) are located directly beneath the developing cortical plate, (ii) frequently have the inverted pyramid shape characteristic of subplate neurons, and (iii) can be labeled by an injection of [3H]thymidine on embryonic day (E) 28, a time when only subplate neurons are being generated. Intense NGFR immunostaining is seen on the cell bodies of these neurons as early as E30, several days after their last round of cell division, and this immunostaining remains strong for approximately 3 weeks. The NGFR immunoreactivity begins to decline around E52 and has disappeared from the region altogether by E60, at which time subplate neurons begin to die. The cellular localization and timing of expression suggest that the NGFR may play a role in the maintenance of subplate neurons and in the maturation of the cerebral cortex.

Aging↗
PubMed2002

Ena/VASP proteins regulate cortical neuronal positioning.

Development of the multilayered cerebral cortex involves extensive regulated migration of neurons arising from the deeper germinative layers of the mammalian brain. The anatomy and formation of the cortical layers has been well characterized; however, the underlying molecular mechanisms that control the migration and the final positioning of neurons within the cortex remain poorly understood. Here, we report evidence for a key role of Ena/VASP proteins, a protein family implicated in the spatial control of actin assembly and previously shown to negatively regulate fibroblast cell speeds, in cortical development. Ena/VASP proteins are highly expressed in the developing cortical plate in cells bordering Reelin-expressing Cajal-Retzius cells and in the intermediate zone through which newly born cells migrate. Inhibition of Ena/VASP function through retroviral injections in utero led to aberrant placement of early-born pyramidal neurons in the superficial layers of both the embryonic and the postnatal cortex in a cell-autonomous fashion. The abnormally placed pyramidal neurons exhibited grossly normal morphology and polarity. Our results are consistent with a model in which Ena/VASP proteins function in vivo to control the position of neurons in the mouse neocortex.

Animals↗
PubMed1999

Consequences of cortical dysplasia during development in rats.

PURPOSE: To determine whether focal cortical dysplasia alters excitability in regions distant to the region of the dysplasia. METHODS: We studied the physiological consequences of cortical dysplasia induced by either one or three freeze lesions at birth. Seizure susceptibility was assessed at age 35 days by amygdala kindling. c-fos immunostaining was performed after kainic acid-induced seizures at 10, 20, or 30 days to evaluate the patterns of neuronal activation. RESULTS: Freeze lesions consistently produced uniform regions of dysplasia. No significant differences in seizure susceptibility, as measured by afterdischarge threshold and kindling rate, were seen between controls and rats receiving either one or three freeze lesions. c-fos activation after kainic acid injection was not observed in the region of the dysplasia. However, rats with freeze lesions at age 30 days demonstrated asymmetric c-fos staining with greater staining in CA1 ipsilateral, than contralateral, to the lesion. CONCLUSIONS: Focal cortical dysplasia results in enhancement of c-fos activation in regions outside the borders of the dysplasia. However, as indicated by kindling rate, the functional consequences of these alterations do not appear to be robust.

Amygdala↗
PubMed2001

Role of thyroid hormones in the maturation and organisation of rat barrel cortex.

The influence of thyroid hormones on cortical development was analysed in rat somatosensory cortex. Maternal and foetal hypothyroidism was induced and maintained by methimazole treatment from embryonic day 13 onwards. 5-Bromo-2'-deoxyuridine (BrdU) labelling in hypothyroid rats showed that cell positioning during corticogenesis followed an inside-out pattern. The radial neurogenetic gradients were more diffuse at all ages with respect to normal rats due to the inappropriate location of many cells, including those of the subcortical white matter. Most (62%) of the cells in the subcortical white matter of hypothyroid rats were labelled at embryonic day 15. Nissl staining of the primary somatosensory cortex showed blurred cortical layer boundaries and an abnormal barrel cytoarchitecture. Cytochrome oxidase and peanut agglutinin staining showed that the tangential organisation of the posteromedial barrel subfield and its layer IV specificity was not lost in hypothyroid rats. However the temporal pattern of peanut agglutinin labelling was delayed 3-4 days with respect to normal rats. In hypothyroid rats, the total barrelfield tangential area was reduced by 27% with respect to normal. The total tangential barrel area, corresponding to peanut agglutinin-negative labelling, occupied 77% of the barrelfield area and only 66% in hypothyroid rats. This reduction was larger with cytochrome oxidase staining where the total barrel area occupied 69% of the barrelfield area in normal and 46% in hypothyroid rats. Our data stress the importance of maternal and foetal thyroid hormones during development, and demonstrate the irreversible effects that maternal and foetal hypothyroidism may have on the intrinsic organisation and maturation of the neocortex.

Animals↗
PubMed1997

Imaging and epilepsy.

MRI has been applied to the investigation of epilepsy for 12 years. The principle role of MRI is in the definition of structural abnormalities that underly seizure disorders. Hippocampal sclerosis may be reliably identified, quantitative studies are useful for research and, in equivocal cases, for clinical purposes. A range of malformations of cortical development (MCD) may be determined. In patients with refractory partial seizures who are candidates for surgical treatment, a relevant abnormality is identifiable using MRI in 85%, it is likely that subtle MCD or gliosis accounts for the majority of the remainder. The proportion of cryptogenic cases will decrease with improvements in MRI hardware, signal acquisition techniques and post-processing methodologies. Functional MRI is used to identify the cerebral areas that are responsible for specific cognitive processes, and is of importance in planning resections close to eloquent cortical areas. Magnetic resonance spectroscopy (MRS) provides a means of investigating cerebral metabolites and some neurotransmitters, non-invasively. The concentrations of N-acetyl-aspartate (NAA), creatine and choline-containing compounds may be estimated using proton MRS. Reduction of the ratio of NAA/(creatine+choline) is a feature of cerebral regions that include epileptic foci. Cerebral concentrations of GABA and glutamate, and the effects of antiepileptic drugs on these, may be estimated. Concentrations of high energy phosphate compounds, inorganic phosphate and pH may be assessed using 31P-MRS. In general, epileptic foci are associated with an increase in pH, increased inorganic phosphate and decreased phosphate monoesters. Carbon-13 spectroscopy promises to be a useful method for investigating cerebral metabolism in vivo. PET may provide data on regional cerebral blood flow (rCBF), glucose metabolism and the binding of specific ligands to receptors. Correlation of functional and structural imaging data is necessary for adequate interpretation. The hallmark of an epileptic focus is an area of reduced glucose metabolism, identified using [18F]fluorodeoxyglucose (18FDG), that is commonly more extensive than the underlying anatomical abnormality. The clinical role of 18FDG-PET requires re-evaluation in the light of the advances in structural imaging with MRI. Specific ligands are used to investigate specific receptors. Benzodiazepine and opioid receptors have been studied most. Reduced benzodiazepine receptor binding is commonly seen at an epileptic focus, in a more restricted distribution than an area of hypometabolism. Focal increases and decreases in benzodiazepine receptor binding have been demonstrated in MCD in areas that appear normal on MRI, indicating the widespread nature of the abnormalities. It has been found that mu-opioid receptors are increased in temporal neocortex overlying mesial temporal epileptic foci. Dynamic studies of ligand-receptor binding are possible using PET, for example the release of cerebral endogenous opioids has been implied at the time of serial absences. The main use of single photon emission computed tomography (SPECT) is to produce images reflecting rCBF. Interictal studies alone are not reliable. A strength of SPECT is the ability to obtain images related to rCBF at the time of seizures. Concomitant video-EEG recording is necessary. Ictal scans need to be considered in comparison with an interictal scan and an MRI. Interpretation must be cautious, but may yield data that is useful in the investigation of patients for possible surgical treatment.

Cerebral Cortex↗
PubMed2000

Astrocytes in culture express the full-length Trk-B receptor and respond to brain derived neurotrophic factor by changing intracellular calcium levels: effect of ethanol exposure in rats.

Although cultured astroglial cells were reported to express exclusively the truncated non-catalytic Trk B receptor for brain-derived neurotrophic factor (BDNF), we detect here, using a sensitive ribonuclease protection assay, mRNAs for both truncated (TrkB-T) and the full length catalytic (TrkB-fl) form of BDNF receptor in developing cortical astrocytes and neurons in culture. Cortical neurons and immature astroglia, such as radial glia and proliferating astrocytes, express both the protein and mRNAs for TrkB-fl and TrkB-T, whereas the differentiation of astrocytes leads to a decrease in the trkB-fl mRNA, being the truncated TrkB the predominant receptor in differentiating and confluent astrocytes. The levels of TrkB-fl expression in proliferating and differentiating astrocytes and neurons correlates with the cell response to BDNF, monitored by the rise in intracellular [Ca(2+)](i). Foetal exposure to ethanol alters astroglial development and delays the reduction in trkB-fl mRNA levels observed with differentiation of astrocytes. These results demonstrate that immature astrocytes are able to express the catalytic Trk B receptors and to respond to BDNF with the activation of conventional signal transduction pathways. The results suggest that this signalling pathway is more activated in ethanol-exposed cells.

Animals↗
PubMed2003

Cortical interneuron fate determination: diverse sources for distinct subtypes?

GABAergic interneurons perform crucial roles in cortical development and function. These roles are executed by a diversity of interneuron subtypes, and abnormal function of particular subtypes has been implicated in a variety of neuropsychiatric diseases. However, little is known about the mechanisms that generate interneuron diversity. This paper discusses the potential origins of interneuron subtypes. Evidence is reviewed that suggests bipolar calretinin expressing interneurons may have distinct origins from those that express parvalbumin or somatostatin. In addition, evidence is presented that migratory cells from the subcortical subventricular zone (SVZ) do not proliferate after migration into the cortical SVZ.

Animals↗
PubMed1992

Different postnatal development of cells expressing mRNA encoding neurotensin receptor.

In situ hybridization histochemistry revealed three different ontogenetic patterns of localized expression of the high-affinity type of neurotensin receptor mRNA in the developing rat brain: one comprises sites which showed transient expression of neurotensin receptor mRNA during the first postnatal week, the expression greatly decreasing thereafter (type I); another comprises sites at which there is a gradual increase in neurotensin receptor mRNA after birth, as there is in cell number and intensity, with advancing age, followed by a plateau (type II); the third comprises sites at which there is much expression of neurotensin receptor mRNA already at birth, and a slight decrease thereafter (type III). The cerebral cortex, except retrosplenial and entorhinal cortices, and the anterior dorsal thalamic nucleus exhibit the type I pattern, while the horizontal and vertical limbs of the diagonal band of Broca, magnocellular preoptic nucleus, substantia innominata, ventral part of the suprachiasmatic nucleus, medial habenular nucleus, ventral tegmental area and substantia nigra pars compacta exhibit the type II pattern. The tenia tecta, retrosplenial and entorhinal cortices exhibit the type III pattern. One of the most striking findings in this study was that the entire neocortex and most of the limbic cortex exhibit the type I pattern, i.e. neurotensin receptor mRNA is expressed transiently long before a neuronal network is established there. This suggests that neurotensin plays an important role in cortical development, other than its reported transmitter-like role in the adult.

Aging↗
PubMed2006

A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia.

BACKGROUND: As a test of plausibility for the hypothesis that schizophrenia can result from abnormal brain, especially cerebral cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, region-dependent reductions in gray matter in cortex and thalamus. METHODS: In offspring of rats administered MAM (22 mg/kg) on E17 or earlier (E15), regional size, neuron number and neuron density were determined in multiple brain regions. Spontaneous synaptic activity at prefrontal cortical (PFC) and ventral striatal (vSTR) neurons was recorded in vivio. Finally, cognitive and sensorimotor processes mediated by frontal and limbic corticostriatal circuits were assessed. RESULTS: Adult MAM-E17-exposed offspring showed selective histopathology: size reductions in mediodorsal thalamus, hippocampus, and parahippocampal, prefrontal, and occipital cortices, but not in sensory midbrain, cerebellum, or sensorimotor cortex. The prefrontal, perirhinal, and occipital cortices showed increased neuron density with no neuron loss. The histopathology was accompanied by a disruption of synaptically-driven "bistable membrane states" in PFC and vSTR neurons, and, at the behavioral level, cognitive inflexibility, orofacial dyskinesias, sensorimotor gating deficits and a post-pubertal-emerging hyper-responsiveness to amphetamine. Earlier embryonic MAM exposure led to microcephaly and a motor phenotype. CONCLUSIONS: The "MAM-E17" rodent models key aspects of neuropathology in circuits that are highly relevant to schizophrenia.

Amphetamine↗
PubMed1998

Focal, continuous spikes suggest cortical developmental abnormalities. Clinical, MRI and neuropathological correlates.

OBJECTIVES: Widespread use of MRI now gives us increased insights into the different expressions of malformations of cortical development (MCD). The heterogeneity of these disorders are reflected by their varied clinical and neuroimaging features. Characteristic and intense scalp EEG abnormalities have been described in some patients. MATERIAL AND METHODS: We report the MRI and clinical findings of 3 adult patients (age 32-36) with a peculiar EEG pattern of distinct, localized, fast, continuous spiking. These patients represent all patients with such EEG findings that have been recognized by the first author during 9 years. RESULTS: MRI showed MCDs in all, respectively hemimegalencephaly, a subcortical heterotopion, and a focal cortical dysgenesis. The EEG findings had been stable since childhood and were posteriorly located. Two patients had fairly well controlled epilepsy in adult age. The third patient was incapacitated by persistent seizures and was treated with surgery. Histologically cortical dysplasia with neuronal clusters was found in this patient. Variable degrees of cognitive dysfunction were present in all. CONCLUSION: Focal, continuous, fast spiking is an unusual scalp EEG pattern. It is not an inevitable sign of severe epilepsy. It may suggest an MCD. It is not yet clear to what extent such findings are predictive of a dysgenetic etiology of epilepsy.

Action Potentials↗
PubMed2001

Epileptogenic networks: cerebral dysplasias and cerebral ectopias.

There are three areas in which functional imaging may be applied to malformations of cortical development (MCD) that give rise to epilepsy: the localization of epileptic activity; the identification of areas of functional abnormality; the mapping of normal cerebral functions, and how these may be displaced. Single photon emission computerized tomography (SPECT) commonly shows interictal hypoperfusion and ictal hyperperfusion. Positron emission tomography (PET), using (18)F-fluorodeoxyglucose, often shows glucose metabolism in ectopic grey matter and hypometabolism in MCD, compared with normal cortex. Cognitive activation tasks, using PET or fMRI, have shown that malformed cortex may participate in cerebral functions, but also widespread atypical cortical organization. Cognitive activation tasks using fMRI are useful when planning surgical resections close to eloquent cortex. Binding of (11)C-flumazenil to central benzodiazepine receptors (cBZR) is often abnormal in MCD, and in areas of cortex that appear normal on MRI, with increased and decreased binding. MR Spectroscopy also reveals abnormalities that are more extensive than the MRI visible lesion, implying more widespread structural and functional abnormalities. The recording of EEG during fMRI has allowed the latter to be used to localize cerebral areas involved in the generation of interictal epileptiform activity. Electroencephalograph source localization and magneto-encephalography may also prove to be useful in the localization of interictal epileptiform activity, particularly when fMRI data are used to constrain the solutions.

Cerebral Cortex↗