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PubMed2005

Cortical neuronal densities and lamination in focal cortical dysplasia.

Focal cortical dysplasia (FCD) is considered to represent a malformation due to abnormal cortical development (MCD) and is an important cause of focal epilepsy. The histopathological features include abnormal laminar architecture, the presence of hypertrophic and dysmorphic neurones in FCD type IIA and additional balloon cells in FCD type IIB. The events causing these sporadic lesions are unknown, but abnormal progenitor cell proliferation occurring late in corticogenesis has been proposed. FCD-like lesions have, however, also been described following a cerebral injury early in life. We carried out a stereological assessment on 15 cases of FCD on NeuN- and Nissl-stained sections from patients with a wide age range, and identified a significant reduction in the neuronal density in all cases in the region of dysplasia compared to the adjacent unaffected cortex (mean neuronal densities 19.2x10(3)/mm3 in the region of dysplasia; 42.8x10(3)/mm3 in the adjacent cortex). Relative differences in neuronal density and size in FCD cases between the superficial (layer I and II) and deep cortical laminae (layer V and VI) were similar to that observed in other pathologies including mild MCD, temporal neocortex adjacent to hippocampal sclerosis as well as in a non-epilepsy surgical control group. The lower overall neuronal densities observed in FCD may reflect neuropil expansion, a local failure of neuronal migration, proliferation or secondary neuronal loss. The preservation of relative differences in neuronal densities between cortical layers and laminar patterns of neurofilament staining in FCD would support the view that the temporal sequence of lamination is not affected.

Adolescent↗
PubMed2003

Effect of developmental sensory and motor deprivation on the functional organization of adult rat somatosensory cortex.

Most sensory systems are active, in the sense that the animal performs specific motor actions in order to collect information of interest-signals are not merely passively received. We, therefore, expect cortical development to depend not only correct sensory experience, but also on correct motor experience. In this study, we used the rat whisker system as a model to compare the importance of these factors. In one group of animals, we trimmed all whiskers starting from post-natal day 8 (P8). In a second group, we left the whiskers intact, but prevented "whisking" by sectioning the facial (VIIth cranial) nerve on P8. The first group had severely disrupted sensory experience but normal motor patterns ("whisker-cut" rats); the second group had normal sensory pathways within which temporal activity patterns were disrupted by motor impairment ("nerve-cut" rats). When they reached 3 months of age, we recorded multi-unit responses from the infragranular layers of primary somatosensory cortex in response to deflection of either single whiskers or pairs of whiskers in order to compare these two groups to a third group of rats that had normal sensory and motor experience. Cortical topographic organization was unaltered in whisker- and nerve-cut rats. Whisker-cut rats showed a smaller than normal difference between the response magnitudes for the principal and surrounding whiskers, as well as stronger than normal interactions between co-active whisker inputs. Responses in nerve-cut rats were nearly indistinguishable from those in normal animals. Thus, unexpectedly, neither pure sensory nor sensorimotor deprivation caused gross functional disruption of SI according to our measures. It appears that abnormal sensory experience leads to alterations in the fine-tuning of cortical properties, but cortex is unexpectedly resistant to the effects of abnormal sensory and sensorimotor experience.

Action Potentials↗
PubMed2006

Localization of the scaffolding protein RACK1 in the developing and adult mouse brain.

RACK1 is a multifunctional scaffolding protein known to be involved in the regulation of various signaling cascades in the central nervous system (CNS). In order to gain insight into the neurological functions of RACK1, we examined the expression of RACK1 mRNA and protein during gestation and in the adult mouse brain. Several expression patterns were observed. At embryonic day 11.5 (E11.5), RACK1 is expressed in a high-dorsal to low-ventral gradient throughout the brain. At E13.5, RACK1 is most abundant in the telencephalon. In the developing cortical primordium, RACK1 protein is expressed in a high-rostromidline to low-caudolateral gradient that appears to be regulated post-transcriptionally. At E18.5, RACK1 is expressed most abundantly in layers 1-4 of the cortex, striatum, hippocampus, dentate gyrus and specific thalamic nuclei. In the adult mouse, RACK1 is ubiquitously expressed in neuronal perikarya in most brain regions, with relatively higher levels in hippocampus, olfactory bulb, cortex and cerebellum. Subcellular staining was detected mainly in the cell bodies and extending into dendrites, whereas RACK1 was not present significantly in axonal fibers or nuclei. We also determined brain regions in which RACK1 interacts with one of its binding partners, the betaII isoform of protein kinase C (betaIIPKC). We found that betaIIPKC had a much more restricted expression pattern than RACK1 and overlapped with the scaffolding protein only in certain regions, including the CA1 area of the hippocampus, cerebellum and striatum. Our results suggest an important role for RACK1 during CNS development and support multiple functions of the protein in the adult brain.

Animals↗
PubMed2004

Successful treatment of tacrolimus (FK506)-related leukoencephalopathy with cerebral hemorrhage in a patient who underwent nonmyeloablative stem cell transplantation.

A 46-year-old woman with Hodgkin's disease who underwent nonmyeloablative allogeneic stem cell transplantation developed cortical blindness, seizures, and left hemiparesis on day 100 while receiving tacrolimus (FK506) and prednisone for the treatment of graft-versus-host disease (GVHD). Magnetic resonance imaging revealed multiple changes, mainly in the bilateral occipital lobes, suggesting FK506-related leukoencephalopathy. These abnormalities improved after discontinuation of FK506. However, 3 days after the episode, cerebral hemorrhage in the left occipital lobe with perforation to the left subdural space occurred. Although FK506-induced leukoencephalopathy with cerebral hemorrhage is considered the more severe form of such leukoencephalopathy, the patient's neurological symptoms almost completely resolved and radiographic findings improved after discontinuation of FK506, tapering of methylprednisolone, and initiation of mycophenolate mofetil. FK506-related leukoencephalopathy is a rare complication after allogeneic stem cell transplantation. Although the symptoms usually subside after discontinuation of FK506, therapeutic intervention in many cases may result in severe complications, including GVHD and vascular disease. We consider it important to use immunosuppressive agents without vascular endothelial toxicity for preventing the development of fatal GVHD after discontinuation of FK506.

Cerebral Hemorrhage↗
PubMed1997

Dysgenesis of the corpus callosum and associated telencephalic anomalies: MRI.

We analysed the MRI findings in 23 patients with callosal dysgenesis in relation to their associated telencephalic anomalies to investigate the morphological significance of the development of Probst's bundles and the anterior commissure in congenital callosal dysgenesis. We classified callosal dysgenesis into three types: total defect (9 patients), partial defect (7) and hypoplasia (7). Associated anomalies were observed in 15 patients, including migration disorder (8 patients), micrencephaly (5), and lipoma (2). The remaining 8 patients had no associated anomalies. Probst's bundles were not identified in 4 patients with a severe migration disorder. An absent or hypoplastic anterior commissure was observed in 9 of the 16 patients with callosal defect and all 7 of those with callosal hypoplasia. Colpocephaly and keyhole dilatation of the temporal horns were seen in 16 and 21 patients, respectively. Callosal dysgenesis may occur not only through a defect in the callosal anlage, but also from impaired growth of axonal fibres projecting from the cerebral isocortex. Therefore, associated telencephalic anomalies may be responsible for additional features in callosal dysgenesis. Consequently, identification of Probst's bundles and the anterior commissure may be important when assessing cortical development in patients with callosal dysgenesis.

Abnormalities, Multiple↗
PubMed1983

Aminophylline and kindled seizures.

The effects of aminophylline on amygdaloid and cortically kindled rats was studied. Rats implanted with chronic amygdaloid electrodes received either saline or 150 mg/kg, i.p., aminophylline 20 min prior to their first stimulation. On the first stimulation, aminophylline-treated rats had dramatically longer afterdischarge durations and more severe seizure ranks. When fully kindled, the animals were retested with saline or aminophylline. Again, the aminophylline-treated animals had longer afterdischarge durations than the saline-treated rats. In a second experiment, fully amygdaloid kindled rats were pretreated with various doses of aminophylline and stimulated 20 min later. With suprathreshold stimulation, a dose-dependent increase was noted in the afterdischarge duration. During seizure threshold determinations, aminophylline pretreatment markedly prolonged afterdischarge durations without significantly changing seizure severity or threshold. When animals were treated with the adenosine agonist, 2-chloroadenosine, prior to kindled amygdaloid stimulation, the elicited afterdischarge was shortened. The effect was antagonized where treatment with both 2-chloroadenosine and aminophylline occurred prior to amygdaloid stimulation. Rats with neocortical electrodes were also exposed to various doses of aminophylline while in a stable, partially developed kindled stage and again when fully kindled. At both stages, afterdischarge duration was increased by aminophylline in a dose-dependent manner. The partially developed, cortically kindled animals were more responsive to aminophylline than were those fully kindled and they tended to have greater increases in afterdischarge duration and seizure rank. These data demonstrate that aminophylline acts to prolong afterdischarges elicited at various stages of kindling from both amygdaloid and cortical sites.

2-Chloroadenosine↗
PubMed2006

Periventricular nodular heterotopia: classification, epileptic history, and genesis of epileptic discharges.

PURPOSE: Periventricular nodular heterotopia (PNH) is among the most common malformations of cortical development, and affected patients are frequently characterized by focal drug-resistant epilepsy. Here we analyzed clinical, MRI, and electrophysiologic findings in 54 PNH patients to reevaluate the classification of PNH, relate the anatomic features to epileptic outcome, and ascertain the contribution of PNH nodules to the onset of epileptic discharges. METHODS: The patients were followed up for a prolonged period at the Epilepsy Center of our Institute. In all cases, we related MRI findings to clinical and epileptic outcome and analyzed interictal and ictal EEG abnormalities. In one patient, EEG and stereo-EEG (SEEG) recordings of seizures were compared. RESULTS: We included cases with periventricular nodules, also extending to white matter and cortex, provided that anatomic continuity was present between nodules and malformed cortex. Based on imaging and clinical data, patients were subdivided into five PNH groups: (a) bilateral and symmetrical; (b) bilateral single-noduled; (c) bilateral and asymmetrical; (d) unilateral; and (e) unilateral with extension to neocortex. The latter three groups were characterized by worse epileptic outcome. No differences in outcome were found between unilateral PNH patients regardless the presence of cortical involvement. Interictal as well as ictal EEG abnormalities were always related to PNH location. CONCLUSIONS: The distinctive clinical features and epileptic outcomes in each group of patients confirm the reliability of the proposed classification. Ictal EEG and SEEG recordings suggest that seizures are generated by abnormal anatomic circuitries including the heterotopic nodules and adjacent cortical areas.

Adolescent↗
PubMed2003

Abnormal thalamocortical pathfinding and terminal arbors lead to enlarged barrels in neonatal GAP-43 heterozygous mice.

GAP-43 has been implicated in axonal pathfinding and sprouting, synaptic plasticity, and neurotransmitter release. However, its effect on cortical development in vivo is poorly understood. We have previously shown that GAP-43 knockout (-/-) mice fail to develop whisker-related barrels or an ordered whisker map in the cortex. Here we used cytochrome oxidase (CO) histochemistry to demonstrate that GAP-43 heterozygous (+/-) mice develop larger than normal barrels at postnatal day 7 (P7), despite normal body and brain weight. Using serotonin transporter (5HT-T) histochemistry to label thalamocortical afferents (TCAs), we found no obvious abnormalities in other somatosensory areas or primary visual cortex of GAP-43 (+/-) mice. However, TCA projections to (+/-) primary auditory cortex were not as clearly defined. To clarify the mechanism underlying the large-barrel phenotype, we used lipophilic (DiI) axon labeling. We found evidence for multiple pathfinding abnormalities among GAP-43 (+/-) TCAs. These axons show increased fasciculation within the internal capsule, as well as abnormal turning and branching in the subcortical white matter. These pathfinding errors most likely reflect failures of signal recognition and/or transduction by ingrowing TCAs. In addition, many DiI-labeled (+/-) TCAs exhibit widespread, sparsely branched terminal arbors in layer IV, reflecting the large-barrel phenotype. They also resemble those found in rat barrel cortex deprived of whisker inputs from birth, suggesting a failure of activity-dependent synaptogenesis and/or synaptic stabilization in (+/-) cortex. Our findings suggest that reduced GAP-43 expression can alter the fine-tuning of a cortical map through a combination of pathfinding and synaptic plasticity mechanisms.

Animals↗
PubMed2004

Severity of histopathologic abnormalities and in vivo epileptogenicity in the in utero radiation model of rats is dose dependent.

PURPOSE: Malformations of cortical development (MCDs) are a frequent cause of refractory epilepsy in humans. The in utero radiation model in rats shares many clinical and histopathologic characteristics with human MCDs. Previous studies reported the presence of clinical seizures in radiated rats, but also suggested a dose-dependent differential effect. METHODS: Time-pregnant Sprague-Dawley rats were irradiated on embryonic day E17 with 100 cGy (low dose), 145 cGy (medium dose), 175 cGy (high dose), or were left untreated. Their adult litters were implanted with bifrontal epidural and hippocampal depth electrodes and underwent long-term video-EEG monitoring. After 2 weeks of monitoring, the animals were killed and their brains processed for histological studies. RESULTS: Spikes were most frequently found in the rats that were subjected to low- and medium-dose radiation at E17 and were less frequently seen in the animals that were subjected to high-dose radiation. No interictal spikes were found in any of the control animals. Seizures were recorded in three of five animals of the medium-dose group. Histological studies showed a dose-dependent decrease in cortical thickness as well as an increase of cortical and hippocampal disorganization. CONCLUSIONS: In vivo epileptogenicity in radiated animals was present only in mild or moderate MCD. No in vivo epileptogenicity was seen in severe radiation-induced MCD.

Abnormalities, Radiation-Induced↗
PubMed2005

Activation of the Notch pathway in Down syndrome: cross-talk of Notch and APP.

Down syndrome (DS) patients suffer from mental retardation, but also display enhanced beta-APP production and develop cortical amyloid plaques at an early age. As beta-APP and Notch are both processed by gamma-secretase, we analyzed expression of the Notch signaling pathway in the adult DS brain and in a model system for DS, human trisomy 21 fibroblasts by quantitative PCR. In adult DS cortex we found that Notch1, Dll1 and Hes1 expression is up-regulated. Moreover, DS fibroblasts and Alzheimer disease cortex also show overexpression of Notch1 and Dll1, indicating that enhanced beta-APP processing found in both DS and AD could be instrumental in these changes. Using pull-down studies we could demonstrate interaction of APP with Notch1, suggesting that these transmembrane proteins form heterodimers, but independent of gamma-secretase. We could demonstrate binding of the intracellular domain of Notch1 to the APP adaptor protein Fe65. Furthermore, activated Notch1 can trans-activate an APP target gene, Kai1, and vice versa, activated APP can trans-activate the classical Notch target gene Hes1. These data suggest that Notch expression is activated in Down syndrome, possibly through cross-talk with APP signaling. This interaction might affect brain development, since the Notch pathway plays a pivotal role in neuron-glia differentiation.

Adult↗
PubMed1997

Bilateral parasagittal parietooccipital polymicrogyria and epilepsy.

We describe 9 patients with a bilateral malformation of cortical development, centered around the parasagittal and mesial aspects of the parietooccipital cortex, with magnetic resonance imaging findings suggestive of polymicrogyria. No familial distribution or etiologic factors were identified. Location in a watershed area between anterior and posterior cerebral arteries suggests postmigratory perfusion failure as the underlying cause. In most patients the malformation was detected by magnetic resonance imaging after computed tomography scans with 10-mm-thick sections were considered normal. Seizures, present in all, had started between the ages of 20 months and 15 years (mean, 9 years) and were intractable in 7. Complex partial seizures with or without minor automatisms were the most frequent ictal pattern. In only 4 patients these were preceded by symptoms indicating posterior onset. Interictal electroencephalograms showed both diffuse and bilateral parietooccipital or temporal abnormalities. The range of IQ scores indicated average intelligence to mild retardation. Several patients presented deficits on neuropsychological tasks requiring performance under time constraints, suggesting that the malformation may result in cognitive slowing. Early diagnosis of this malformation may be difficult because of the lack of neurological signs, relatively late seizure onset, difficulty in localizing seizure onset, and inability to recognize the cortical abnormality on computed tomography scans.

Adolescent↗
PubMed1995

Cajal-Retzius neurons in human cerebral cortex at midgestation show immunoreactivity for neurofilament and calcium-binding proteins.

Along with subplate neurons, Cajal-Retzius cells (CRc) are the first neurons to be generated in the cortical anlage. Studies of their chemical content, such as neurofilament and calcium-binding proteins, might give indications on their role in cortical development at midgestation in human fetuses (20-24 gestation weeks), when the CRc are morphologically mature. Cajal-Retzius cells were immunolabeled with antibodies to subunits of neurofilament proteins SMI31 and SMI32. The SMI32 antibodies (directed against the nonphosphorylated epitope) specifically labeled the CR cell bodies, dendrites, and proximal axons in a Golgilike fashion. Specific acetylcholinesterase activity is known to be typical of all the CRc, and double labeling for SMI32 immunoreactivity and acetylcholinesterase histochemistry demonstrated that all the CRc exhibited SMI32 immunoreactivity. The SMI31 antibodies (directed against the phosphorylated epitope) exclusively labeled the CRc axons, forming a dense positive network in the deep one-half of layer 1. This plexus was much denser than the one described with the Golgi method (Marin-Padilla, 1990: J. Comp Neurol 239:89-105). Calbindin D28k, parvalbumin, and calretinin immunoreactivities were visualized in the CRc. Double-labeling experiments showed that most of the CRc contained both calbindin and calretinin and sometimes parvalbumin. These colocalizations revealed a chemical heterogeneity within the CRc population even though they were described as morphologically homogeneous. These colocalizations of calcium-binding proteins in the CRc differed from the other nonpyramidal cortical neurons where calbindin, calretinin, and parvalbumin are contained in different (mutually exclusive) neuronal populations. Based on the morphological features and differential chemical contents described for the CRc, different hypotheses on their possible role and fate are discussed.

Acetylcholinesterase↗
PubMed1988

Development of somatostatin immunoreactive neurons in the rat occipital cortex: a combined immunocytochemical-autoradiographic study.

The postnatal development of somatostatin (SRIF)-immunoreactive neurons, previously labeled with [3H]thymidine on embryonic days E14-E22, has been studied in the rat occipital cortex. Immunocytochemistry combined with autoradiography showed an "inside-out" maturation pattern. Only SRIF neurons generated at E14 were present in layer VI in newborn rats. Later generated SRIF neurons appeared progressively higher in the cortex until about postnatal day 12 when SRIF neurons from E21 appeared in layer II. At 2 weeks of age, therefore, all SRIF neurons from E14-E21 were present. Most of these had been generated between E15 and E17 with a moderate number at E14 and rapidly diminishing numbers from E18 to E21. Although an overall layered distribution was apparent at peak production, there was a tendency for diffuse distribution most noticeable at E17. Diffusely distributed neurons were more likely to be below their appropriate layer than above it, thus contributing extra SRIF neurons to layer VI. At 3, 4, and 5 weeks, progressively fewer SRIF neurons were seen with a consequent reduction in the number of double-labeled neurons. It is suggested that the transient population of SRIF neurons thus revealed plays a role in cortical development.

Animals↗
PubMed1999

Changing properties of GABA(A) receptor-mediated signaling during early neocortical development.

Evidence from several brain regions suggests gamma-aminobutyric acid (GABA) can exert a trophic influence during development, expanding the role of this amino acid beyond its function as an inhibitory neurotransmitter. Proliferating precursor cells in the neocortical ventricular zone (VZ) express functional GABA(A) receptors as do immature postmigratory neurons in the developing cortical plate (CP); however, GABA(A) receptor properties in these distinct cell populations have not been compared. Using electrophysiological techniques in embryonic and early postnatal neocortex, we find that GABA(A) receptors expressed by VZ cells have a higher apparent affinity for GABA and are relatively insensitive to receptor desensitization compared with neurons in the CP. GABA-induced current magnitude increases with maturation with the smallest responses found in recordings from precursor cells in the VZ. No evidence was found that GABA(A) receptors on VZ cells are activated synaptically, consistent with previous data suggesting that these receptors are activated in a paracrine fashion by nonsynaptically released ligand. After neurons are born and migrate to the CP, they begin to demonstrate spontaneous synaptic activity, the majority of which is GABA(A) mediated. These spontaneous GABA(A) postsynaptic currents (sPSCs) first were detected at embryonic day 18 (E18). At birth, approximately 50% of recordings from cortical neurons demonstrated GABA(A)-mediated sPSCs, and this value increased with age. GABA(A)-mediated sPSCs were action potential dependent and arose from local GABAergic interneurons. GABA application could evoke action potential-dependent PSCs in neonatal cortical neurons, suggesting that during the first few postnatal days, GABA can act as an excitatory neurotransmitter. Finally, N-methyl-D-aspartate (NMDA)- but not non-NMDA-mediated sPSCs were also present in early postnatal neurons. These events were not observed in cells voltage clamped at negative holding potentials (-60 to -70 mV) but were evident when the holding potential was set at positive values (+30 to +60 mV). Together these results provide evidence for the early maturation of GABAergic communication in the neocortex and a functional change in GABA(A)-receptor properties between precursor cells and early postmitotic neurons. The change in GABA(A)-receptor properties may reflect the shift from paracrine to synaptic receptor activation.

Animals↗
PubMed2002

Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin signaling.

Two major signaling pathways that control neuronal positioning during brain development have been uncovered as a result of genetic and biochemical studies on neurological mouse mutants. Mice deficient in Reelin, Disabled 1 (Dab1), or both the very low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor 2 (ApoER2) exhibit identical neuroanatomic defects in laminar structures throughout the brain. These proteins function as components of the Reelin signaling pathway. Reelin is a secreted glycoprotein that binds to VLDLR and ApoER2, inducing tyrosine phosphorylation of Dab1, an intracellular adapter protein. Neuronal migration is also regulated by cyclin-dependent kinase 5 (Cdk5) and its activating subunits p35 and p39. Mice deficient in Cdk5, p35, or both p35 and p39 exhibit lamination defects that are similar but not identical to those observed in mice with a defect in the Reelin signaling pathway. Cdk5 phosphorylates proteins that maintain cytoskeletal structures and promote cell motility. To explore the possibility that Cdk5 influences the Reelin pathway, we sought to determine whether Dab1 is a substrate for Cdk5. Here we show that Cdk5 phosphorylates Dab1 on serine 491 in vitro and in vivo, independently of Reelin signaling. We also show that ectopic neurons in Cdk5-deficient mice exhibit reduced levels of Reelin signaling during later stages of cortical development, although Cdk5 is not required for Reelin-induced tyrosine phosphorylation of Dab1. Although the functional significance of Dab1 serine phosphorylation is unclear, our results suggest that there is biochemical cross-talk between two signaling pathways that control cell positioning.

Amino Acid Sequence↗
PubMed2002

Analysis of the cerebral cortex in holoprosencephaly with attention to the sylvian fissures.

BACKGROUND AND PURPOSE: Analysis of specific features in the brain of patients with holoprosencephaly (HPE) may clarify normal and abnormal brain development and help predict outcomes for specific children. We assessed sulcal and gyral patterns of cerebral cortex in patients with HPE and developed a method of grading brain development. METHODS: Neuroimaging studies (75 MR imaging, 21 CT) of 96 patients with HPE were retrospectively reviewed, with specific attention paid to the cerebral cortex. Thickness of cortex, width of gyri, and depth of sulci were assessed subjectively and by measurement. The angle between lines drawn tangential to the sylvian fissures ("sylvian angle") was measured in each patient with HPE and in 20 control patients. RESULTS: Thickness of cortex was normal in all 96 patients. Gyral shape and width and sulcal depth were normal in 80 patients. Twelve patients, all with very severe HPE and microcephaly, had reduced sulcal depth, diffusely in eight and limited to the anteromedial cortex in four with lobar HPE. Four patients had subcortical heterotopia, located anterior to the interhemispheric fissure, associated with shallow sulci in the overlying cortex. Sylvian fissures were displaced further anteriorly and medially as HPE became more severe, until, in the most severe cases, no sylvian fissures could be identified. Sylvian angle measurements corresponded closely with severity of HPE, being largest in the most severe and smallest in the least severe cases. All patients with HPE had sylvian angles significantly larger than the mean of 15 degrees measured in the control patients. CONCLUSION: The only true malformations of cortical development were subcortical heterotopia. However, diffuse and focal abnormal sulci were observed. We propose our sylvian angle measurement of extent of frontal lobe development as an objective means of quantifying the severity of HPE.

Cerebral Cortex↗
PubMed2005

Neuronal migration in developmental disorders.

Normal central nervous system development is dependent on extensive cell migration. Cells born in the proliferative ventricular zone migrate radially along specialized glial processes to their final locations. In contrast, most inhibitory interneurons found in the adult mammalian cerebral cortex and some other structures migrate along a nonradial pathway and on substrates only recently defined. Defects in radial cell migration have been implicated in several distinct human syndromes in which patients often present with epilepsy and mental retardation and have characteristic cerebral abnormalities. The identification of several genes responsible for human neural cell migration defects has led to a better understanding of the cellular and molecular interactions necessary for normal migration and the pathogenesis of these disorders. The prototypic cell migration disorder in humans is type I lissencephaly. Although type 1 lissencephaly is clearly a defect in radial cell migration, recent data from two model systems (Lis1 and ARX mutant mice) indicate that a defect in non-radial cell migration also exists. Thus, the result of a LIS1 mutation appears to have broader implications than a radial cell migration defect alone. Furthermore, it is likely that the observed defect in non-radial cell migration contributes to the clinical phenotype observed in these patients. Herein we discuss the role of normal non-radial cell migration in cortical development, as well as how perturbations in both radial and nonradial migration result in developmental anomalies.

Brain Diseases↗
PubMed1995

Glial-like cells of the rat pituitary intermediate lobe change morphology and shift from vimentin to GFAP expression during development.

This study demonstrated morphological changes in glial-like cells of the rat pituitary intermediate lobe during early postnatal development, and a subsequent shift in protein expression from vimentin to GFAP. Vimentin immunoreactivity was detected in the lobe at embryo day 14 and was localized in radially-oriented, bipolar cells whose processes spanned the thickness of the intermediate lobe. At electron microscopical resolution, processes contained intermediate filaments, cell nuclei were indented while secretory vesicles characteristic of the endocrine cells were not found. Vimentin immunoreactive intensity began to decrease at postnatal day 5. By postnatal day 7, vimentin-positive, stellate cells were observed, with few radial processes found by day 10. The intensity of vimentin immunoreactivity decreased through day 25. Within the lobe parenchyma, vimentin was localized in glial-like cells since double-label immunohistochemistry revealed no colocalization of beta-endorphin and vimentin, or fibronectin and vimentin. Dopamine-containing axons were in close apposition to vimentin-positive processes. GFAP immunoreactivity first appeared on postnatal day 20 and, by day 25, stellate cell bodies with three to six extended processes were evident. Cells were primarily distributed in the caudal third of the lobe. The characteristic adult pattern of cell clusters in latero-dorsal and ventral portions of the lobe was fully established by postnatal day 55. The transition from vimentin to GFAP expression and concurrent morphological changes resemble those described for radial glial during cerebral cortical development.

Animals↗