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PubMed2006

Alterations in medial prefrontal cortical activity and plasticity in rats with disruption of cortical development.

BACKGROUND: Psychiatric disorders such as schizophrenia are believed to emerge from an interaction of several factors. Thus, a genetic predisposition can lead to developmental compromises that may leave the system more susceptible to deficits induced by subsequent environmental variables such as stress. METHODS: The impact of neurodevelopmental interruption induced by exposure of rats prenatally to a compound methylazoxymethanol acetate (MAM) that disrupts neuronal proliferation was investigated using in vivo electrophysiologic recordings from the prefrontal cortex of adult rats. RESULTS: Prenatal exposure to MAM resulted in alterations in the medial prefrontal cortex indicative of a compromise in information processing. Specifically, we observed a disruption in activity patterns consistent with deficits in neuronal synchronization and abnormal augmentation of synaptic plasticity that was more severely disrupted by stress exposure than in normal animals. Furthermore, these deficits could be reversed by manipulating the mesocortical dopamine system. CONCLUSIONS: These results suggest that disruption of early cortical development causes impairments in medial prefrontal cortical function at adulthood that are more vulnerable to disruptive influences, despite the presence of only subtle structural alterations in the brain.

Action Potentials↗
PubMed2002

Role of functional magnetic resonance imaging in the evaluation of patients with malformations caused by cortical development.

As functional MR imaging (fMRI) continues to offer unparalleled advantages in probing neural activity, diagnostic applications continue to flourish. The evaluation of malformations caused by abnormalities of cortical development is an area in which fMRI has an emerging role and potential to provide new insights into epileptogenesis through multimodal integration with electroencephalagraphy. The clinical impact, however, is just beginning to be felt as new data emerge.

Brain Mapping↗
PubMed2003

[Effect of intracellular-free Ca2+ concentration on transient magnesium-free treatment induced epileptic injury in developing cortical neurons of rats].

OBJECTIVE: To investigate the effect of intracellular-free Ca2+ concentration ([Ca2+]i) on injury following transient Mg(2+)-free treatment in vitro in developing cortical neurons. METHODS: Embryo cortical neurons of rats cultured for 6 d and 17 d were directly exposed to Mg(2+)-free media, or pretreated with NMDA receptor antagonists or calcium channel antagonist before being exposed to Mg(2+)-free media. MTT assay was used to study the injury of neurons. [Ca2+]i were measured using fluo-3, a fluorescent calcium-sensitive dye and laser-scanning confocal microscope, and calculated by the fluorescent intensity. RESULTS: Compared with control, MTT conversion rates decreased after transient (3 h) Mg(2+)-free treatment in neurons cultured for 6 d and 17 d in vitro, (59.1 +/- 6.87)% and (51.2 +/- 5.90)%, respectively. In neurons pre- and co-treated with 10 mumol.L-1 MK-801, 50 mumol.L-1 AP-5 and 10 mumol.L-1 nifedipine, MTT conversion rates were higher than those of neurons with only Mg(2+)-free treatment. Peak values of [Ca2+]i in neurons cultured for 6 d and 17 d were 2.4 +/- 0.23 and 3.2 +/- 0.32, respectively. Peak value of neurons 17 d in vitro was significantly higher than that of neurons 6 d in vitro (P < 0.05). In neurons pre- and co-treated with MK-801, AP-5 and nifedipine, [Ca2+]i were lower than those of neurons with only Mg(2+)-free treatment. CONCLUSION: Neuronal injury and [Ca2+]i changes following Mg(2+)-free-treatment-induced seizure were different between neurons 6 d and 17 d in vitro. It suggested that the age-dependent [Ca2+]i changes might play a role in an age-dependent manner of injury following Mg(2+)-free-treatment-induced seizure. NMDA receptor-Ca2+ pathway activation was crucial in the [Ca2+]i change and the cellular injury induced by Mg(2+)-free treatment.

Aniline Compounds↗
PubMed1996

Dual action of a carbohydrate epitope on afferent and efferent axons in cortical development.

During development of the mammalian cerebral cortex, ingrowing afferents from the thalamus take a path that is different from that of axons leaving the cortical plate. Thalamic axons arrive at the cortex at the time before their target cells of layer 4 are generated in the ventricular zone, but they invade the cortex only shortly before these cells have migrated to their final position in the cortex. Growth-promoting molecules are up-regulated in the developing cortical plate during this period. To identify such molecules, we have generated monoclonal antibodies against membrane preparations from rat postnatal cortex. In Western blots, one antibody (mAb 10) recognized a carbohydrate epitope of a glycoprotein with an apparent molecular weight extending from 180 to 370 kDa. Immunohistochemical staining revealed that the staining pattern of mAb 10 at embryonic stages delineates the pathway of thalamocortical axons, with only very faint labeling of the corticofugal pathway. In vitro assays in combination with time-lapse imaging indicated that mAb 10 has opposite effects on the growth of thalamic and cortical axons. The growth speed and axonal elongation of thalamic fibers on postnatal cortical membranes preincubated with mAb 10 was reduced compared with untreated cortical membranes. In contrast, cortical axons grew faster and stopped their growth less frequently after addition of mAb 10 to a cortical membrane substrate. Taken together, these results suggest that a carbohydrate moiety of a membrane-associated glycoprotein plays a role in the segregation of afferent and efferent cortical axons in the white matter. Moreover, the epitope recognized by mAb 10 might also contribute to regulation of the timing of the thalamocortical innervation at later developmental stages.

Aging↗
PubMed2001

Central benzodiazepine receptors in malformations of cortical development: A quantitative study.

We calculated [(11)C]flumazenil volume of distribution ([(11)C]FMZ-V(d)) after correction for partial volume effect in 10 patients with malformations of cortical development (MCDs) and partial seizures, to quantify the GABA(A)-central benzodiazepine receptor complex. Abnormal grey matter and adjacent or overlying cortex were outlined individually and added to an individualized anatomical template for correction for partial volume effect. Nine of 10 patients showed single or multiple increases or decreases in [(11)C]FMZ-V(d) in or around MCDs. Two of three patients with band heterotopia showed multiple increases in the overlying cortex. In three of four patients with subependymal nodular heterotopia, nodules had lower [(11)C]FMZ-V(d) than the overlying cortex, which was normal. Decreases in [(11)C]FMZ-V(d) were found in two of three clefts and one of six adjacent regions in one schizencephalic patient; another had normal [(11)C]FMZ-V(d) in the thickened cortex itself but increases in all adjacent regions. Binding was reduced within focal cortical dysplasia but increased in adjacent cortex. [(11)C]FMZ-V(d) was normal within one patient's polymicrogyric cortex but increased in one of six adjacent volumes of interest. The localization of abnormalities correlated with EEG and clinical data in cortical MCDs. Flumazenil binding was decreased in some MCDs with increased grey matter volume and increased in some adjacent or overlying areas of normal-appearing cortex, suggesting functional abnormalities beyond MRI- detectable structural changes.

Adolescent↗
PubMed2003

Mapping of spikes, slow waves, and motor tasks in a patient with malformation of cortical development using simultaneous EEG and fMRI.

We report on the simultaneous and continuous acquisition of EEG and functional MRI data in a patient with a left hemiparesis and focal epilepsy secondary to malformation of cortical development in the right hemisphere. EEG-triggered fMRI localization was previously demonstrated in this patient. In the experiments reported here, 322 spikes maximum at electrode C4 and 126 focal slow waves were identified offline. A hierarchy of models was explored in order to assess the relative contributions of each type of EEG event. Modeling the BOLD response to C4 spikes alone showed an area of activation within the large malformation, adjacent to the area of infolding cortex. However, also modeling slow-waves gave rise to a broader and stronger activation, suggesting that the generators overlap. Motor mapping of the right hand showed activation in the left sensorimotor cortex; left-hand tapping led to a more diffuse area of activation, displaced superiorly into the superior frontal gyrus, and a small area of activation within the lesion. In conclusion, continuous EEG-fMRI is useful to compare the functional mapping of epileptiform activity and eloquent cortices in individual patients.

Adult↗
PubMed2004

Expression and cellular distribution of high- and low-affinity neurotrophin receptors in malformations of cortical development.

An increasing number of observations suggests an important and complex role for both high- (tyrosine kinase receptor, trk) and low- (p75) affinity neurotrophin receptors (NTRs) during development in human brain. In the present study, the cell-specific distribution of NTRs was studied in different developmental lesions, including focal cortical dysplasia (FCD, n = 15), ganglioglioma (GG, n = 15) and dysembryoplastic neuroepithelial tumors, (DNT, n = 10), from patients with medically intractable epilepsy. Lesional, perilesional, as well as normal brain regions were examined for the expression of trkA, trkB, trkC and p75(NTR) by immunocytochemistry. In normal postmortem human cortex, immunoreactivity (IR) for trk and p75(NTR) was mainly observed in pyramidal neurons, whereas no notable glial IR was found within the white matter. All three trk receptors were encountered in high levels in the neuronal component of the majority of FCD, GG and DNT specimens. Strong trkA, trkB and trkC IR was found in neurons of different size, including large dysplastic neurons and balloon cells in FCD cases. In contrast, p75(NTR) IR was observed in only a small number of neuronal cells, which also contain trk receptors. Glial cells with astrocytic morphology showed predominantly IR for trkA in FCD and GG specimens, whereas oligodendroglial-like cells in DNT showed predominently IR for trkB. P75(NTR) IR was observed in a population of cells of the microglial/macrophage lineage in both FCD and glioneuronal tumors. Taken together, our findings indicate that the neuronal and the glial components of malformations of cortical development express both high- and low-affinity NTRs. Further research is necessary to investigate how activation of these specific receptors could contribute to the development and the epileptogenicity of these developmental disorders.

Adolescent↗
PubMed2005

Intrapartum complications associated with malformations of cortical development.

Birth asphyxia can be an early sign of cerebral palsy, the effect of an antenatal anomaly rather than its cause. The objective of this study was to evaluate the occurrence of intrapartum complications in patients with malformation of cortical development. The data were retrospectively assessed and compared with a control group of children with idiopathic epilepsy. Intrapartum complications were reported in 22 (31.5%) patients, as opposed to only 2 in the control group (p < 0.001). Patients with cortical malformations frequently present intrapartum complications, which could lead to the misdiagnosis of hypoxic-ischemic encephalopathy.

Adolescent↗
PubMed1998

[Epilepsy and disorders of cortical development in children with congenital cytomegalovirus infection].

INTRODUCTION: Neuroimaging and experimental studies have related cytomegalovirus (CMV) to certain neuronal migration disorders. MATERIAL AND METHODS: To define the electroclinical picture of children with epilepsy associated with disorders of cortical development (DCD) and congenital CMV infection, we conducted a clinical, electroencephalographic and neuroradiological study of 10 children with this condition. RESULTS: Eighty per cent of them had dismorphic traits, or malformations outside CNS. All showed other neuroradiological signs (cerebral calcification, white matter damage, porencephaly). Six patients with bihemispheric DCD (agyria-pachigyria, 2; 'poligyria', 1; schizencephaly, 1; bilateral opercular DCD, 2) showed: Tetraparesis, severe or profound mental deficiency, early onset epilepsy (mean age at onset: 11 months) with spasms, tonic seizures, partial seizures, and multifocal paroxysms or unusual diffuse sharp Alfa-Beta EEG activity. One child developed Epilepsia Partialis Continua. Children with bilateral opercular DCD evolved to a continuous spike and wave (SW) electrical status during wakefulness and sleep, linked to a worsening of psychomotor derangement. Four patients with unilateral hemispheric DCD (pachigyric or 'poligyric') showed: Congenital hemiparesis, mild intellectual deficiency, motor seizures (orofacial, hemiclonic, generalized) beginning in the third year of live, atypical absences with focal phenomena, frequent focal rhythmic SW discharges during wakefulness, and continuous SW status during sleep (CSWS). CONCLUSIONS: A wide spectrum of DCD due to congenital CMV infection is documented. Characteristic electroclinical pictures related to the extent and topographical distribution of the DCD are recognized, which may lead to an appropriate diagnosis and prognosis.

Basal Ganglia↗
PubMed2006

Genetic malformations of cortical development.

The malformations of the cerebral cortex represent a major cause of developmental disabilities, severe epilepsy and reproductive disadvantage. The advent of high-resolution MRI techniques has facilitated the in vivo identification of a large group of cortical malformation phenotypes. Several malformation syndromes caused by abnormal cortical development have been recognised and specific causative gene defects have been identified. Periventricular nodular heterotopia (PNH) is a malformation of neuronal migration in which a subset of neurons fails to migrate into the developing cerebral cortex. X-linked PNH is mainly seen in females and is often associated with focal epilepsy. FLNA mutations have been reported in all familial cases and in about 25% of sporadic patients. A rare recessive form of PNH due ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay and early seizures. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) are disorders of neuronal migration and represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior SBH owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Mutations of DCX have also been found in male patients with anterior SBH and in female relatives with normal brain magnetic resonance imaging. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene. X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene. Affected boys have severe delay and seizures with suppression-burst EEG. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dominant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy. Recessive bilateral frontoparietal polymicrogyria has been associated with mutations of the GPR56 gene. Epilepsy is often present in patients with cortical malformations and tends to be severe, although its incidence and type vary in different malformations. It is estimated that up to 40% of children with drug-resistant epilepsy have a cortical malformation. However, the physiopathological mechanisms relating cortical malformations to epilepsy remain elusive.

Cerebral Cortex↗
PubMed2004

Subtraction SPECT coregistered to MRI in focal malformations of cortical development: localization of the epileptogenic zone in epilepsy surgery candidates.

PURPOSE: To determine the extent to which periictal subtraction single-photon emission computed tomography (SPECT) may improve detection and definition of the epileptogenic zone in patients with focal malformations of cortical development (MCDs). METHODS: Subtraction SPECT coregistered to magnetic resonance (MR) images (SISCOM) were constructed for 22 consecutive patients with focal MCDs who underwent periictal SPECT injection (18 ictal and four postictal). In the 17 patients who had epilepsy surgery, concordance between the site of SISCOM localization and site of surgical resection was determined by coregistration of SISCOM images with postoperative MRIs. RESULTS: SISCOM images were localizing in 19 (86%) patients, including eight of the 10 with nonlocalizing MRI. Concordance of SISCOM localization was 91% with MRI localization, 93% with scalp ictal EEG localization, and 100% with intracranial EEG localization. Eight patients whose SISCOM localization was concordant with the surgical resection site had lower postoperative seizure frequency scores (SFSs; p = 0.04) and greater postoperative improvement in SFSs (p = 0.05) than the nine patients whose SISCOM was either nonconcordant or nonlocalizing. On multiple regression analysis, a model combining SISCOM concordance with surgical resection site and extent of MRI lesion resection was predictive of postoperative SFS (R2 = 0.47; p = 0.03). CONCLUSIONS: Periictal subtraction SPECT using the SISCOM technique provides useful information for seizure localization in patients with focal MCDs, even when MRI is nonlocalizing.

Adolescent↗
PubMed2006

Localization of glutamate receptors in developing cortical neurons in culture and relationship to susceptibility to excitotoxicity.

Overactivation of glutamate receptors leading to excitotoxicity has been implicated in the neurodegenerative alterations of a range of central nervous system (CNS) disorders. We have investigated the cell-type-specific changes in glutamate receptor localization in developing cortical neurons in culture, as well as the relationship between glutamate receptor subunit distribution with synapse formation and susceptibility to excitotoxicity. Glutamate receptor subunit clustering was present prior to the formation of synapses. However, different receptor types showed distinctive temporal patterns of subunit clustering, localization to spines, and apposition to presynaptic terminals. N-methyl-D-aspartate (NMDA) receptor subunit immunolabelling was present in puncta along dendrites prior to the formation of synapses, with relatively little localization to spines. Vulnerability to NMDA receptor-mediated excitotoxicity occurred before receptor subunits became localized in apposition to presynaptic terminals. Clustering of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors occurred concurrently with development of vulnerability to excitotoxicity and was related to localization of AMPA receptors at synapses and in spines. Different AMPA receptor subunits demonstrated cell-type-specific localization as well as distribution to spines, dendrites, and extrasynaptic subunit clusters. A subclass of neurons demonstrated substantial perineuronal synaptic innervation, and these neurons expressed relatively high levels of GluR1 and/or GluR4 at receptor puncta, indicating the presence of calcium-permeable AMPA receptors and suggesting alternative synaptic signalling mechanisms and vulnerability to excitotoxicity. These data demonstrate the relationship between glutamate receptor subunit expression and localization with synaptogenesis and development of neuronal susceptibility to excitotoxicity. These data also suggest that excitotoxicity can be mediated through extrasynaptic receptor subunit complexes along dendrites.

Animals↗
PubMedDate not supplied

Serotonergic regulation of somatosensory cortical development: lessons from genetic mouse models.

Monoaminergic neurotransmitter systems appear early during embryogenesis, suggesting that they could play important roles in brain development. Accumulated evidence indicates that serotonin (5-hydroxytryptamine, 5-HT) regulates neural as well as nonneural development, including early aspects of embryonic development, differentiation of neuronal progenitors, and morphogenesis of the craniofacial region, heart and limb. Recent studies using monoamine oxidase-A (MAO-A), 5-HT transporter, vesicular monoamine transporter-2 (VMAT2) and 5-HT1B receptor single, double and triple knockout mice have provided evidence that the serotonergic system plays important roles in barrel field formation in the developing somatosensory cortex. Here we review evidence from these genetic mouse models and, based on the accumulated evidence, propose a testable model for future studies of mechanisms underlying serotonergic regulation of cortical development.

Animals↗
PubMed2005

Effects of synaptic activity on dendritic spine motility of developing cortical layer v pyramidal neurons.

It is increasingly clear that dendritic spines play an important role in compartmentalizing post-synaptic signals and that their dynamic morphological properties have functional consequences. Here, we examine this issue using two-photon microscopy to characterize spine motility on layer V pyramidal neurons in acute slices of the developing mouse cortex. In this system, all spine classes except filopodia become less dynamic as development proceeds. General manipulations of activity (TTX or KCl treatment) do not alter spine dynamics, although increased glutamatergic transmission (AMPA or NMDA treatment) stabilizes developing cortical spines. These effects on spine dynamics do not appear to be related to AMPA or NMDA receptor expression as assessed with immunolabeling, as there is no correlation between spine motility and AMPA (GluR1/2) or NMDA (NR1/NR2B) receptor subunit expression on a spine by spine basis. These results indicate that activity through glutamatergic synapses is important for regulating spine motility in the developing mouse cortex, and that the relative complement of receptors, while different across morphological classifications, cannot account for differences in dynamic structural changes in dendritic spines.

Actins↗
PubMed2002

The use of subdural grids in the management of focal malformations due to abnormal cortical development.

Because of the spatial limitations of scalp electroencephalographic recordings and the lack of reproducible results using functional MR imaging techniques to map various eloquent areas of the cortex, the accurate mapping of the extent of epileptogenicity and function currently are best accomplished through invasive electrocorticographic recordings and direct cortical stimulation, respectively. The purpose of this article is to give an overview of the presurgical diagnostic tools used in patients with suspected malformations caused by abnormalities of cortical development with special emphasis on subdural electrodes. The indications and the role of invasive subdural electrode evaluation are discussed.

Brain Mapping↗
PubMed2000

Kainic acid-induced neurotrophic activities in developing cortical neurons.

Using primary cultured cortical neurons from embryonic rat brains, we elucidated an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainic acid (KA) receptor-mediated neuroprotective mechanism through actions of nerve growth factor (NGF) in developing neurons. Neurotoxicity of KA in early days in vitro neurons was quite low compared with the mature neurons. However, pretreatment with anti-NGF antibody or TrkA inhibitor AG-879 profoundly raised KA toxicity. Furthermore, KA stimulation resulted in an increase of TrkA expression and phosphorylation, which was blocked not only by the AMPA/KA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and AG-879, but also by the phospholipase C inhibitor U73122 and the intracellular calcium chelator BAPTA. A study of polyphosphoinositide turnover showed that KA-stimulated phospholipase C (PLC) activity was directly triggered by the AMPA/KA receptor activity, but not by the activity of TrkA or other excitatory amino acid receptor subtypes. Sources of KA-increased intracellular calcium levels were contributed by both extracellular calcium influx and intracellular calcium release and were partially sensitive to guanosine 5'-O-(2-thiodiphosphate). These results indicate that in developing cortical neurons, activation of AMPA/KA receptors by KA may induce expression, followed by activation of TrkA via PLC signaling and intracellular calcium elevation and hence increase reception of NGF on KA-challenged neurons. A G protein-coupled AMPA/KA receptor may be involved in these metabotropic events for neuronal protection.

2-Amino-5-phosphonovalerate↗
PubMed2006

Involvement of the myelin-associated inhibitor Nogo-A in early cortical development and neuronal maturation.

Nogo-A is a myelin-associated protein expressed by neurons and myelinating mature oligodendrocytes in the central nervous system. Although most research has focused on the participation of Nogo-A in the prevention of axonal regeneration and plasticity in the adult, little attention has been paid to the putative functions of Nogo-A during embryonic development. Here we examined the general pattern and cell-specific distribution of Nogo-A in the prenatal mouse telencephalon. In addition, we studied the development of the major axon tracts and radial and tangential migration in Nogo-A/B/C knockout mice. The pattern of Nogo-A showed distinct distribution in radial glia and postmitotic neurons, in which it is particularly enriched in developing axons. Similarly, Nogo-A was enriched at the leading process of tangentially migrating interneurons but not detectable in radial migrating neurons. Although a low level of Nogo-A appears to be on the surface of many cortical neurons, most proteins have intracellular localization. In Nogo-deficient background, neurons displayed early polarization and increased branching in vitro, probably reflecting a cell-intrinsic role of Nogo proteins in branching reduction, and early tangential migration was delayed. On the basis of these observations, we propose that Nogo proteins, particularly Nogo-A, are involved in multiple processes during cortical development.

Aging↗
PubMed2004

Cortical development deNUDEd.

The development of the cerebral cortex is a highly orchestrated process of cell division and migration. In this issue of Neuron, Feng and Walsh and Shu et al. examine the roles of two related proteins, Nde1 (mNudE) and Ndel1 (NUDEL), in cortical development. These proteins play a crucial role in centrosome positioning, with Nde1 functioning mainly during progenitor cell divisions and Ndel1 functioning in neuronal migration.

Animals↗