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PubMed2003

Redox regulation of neuronal migration in a Down Syndrome model.

Down Syndrome (DS), one of the major genetic causes of mental retardation, is characterized by disrupted corticogenesis produced, in part, by an abnormal layering of neurons in cortical laminas II and III. Because defects in the normal migration of neurons during corticogenesis can result in delayed cortical radial expansion and abnormalities in cortical layering, we have examined neuronal migration in murine trisomy 16 (Ts16), a mouse model for DS. Using an in vitro assay for chemotaxis, our data demonstrate that the number of acutely dissociated Ts16 cortical neurons migrating in response to glutamate or N-methyl-D-aspartate (NMDA), known chemotactic factors, was decreased compared to normal littermates, suggesting a defect in NMDA receptor- (NMDAR-) mediated events. Ts16 neurons did not lack NMDAR since expression of mRNA and protein for NMDAR subunits was observed in Ts16 cells. However, the number of cells that generated an observable current in response to NMDA was decreased compared to normal littermates. Similar to DS, Ts16 CNS demonstrated an inherent oxidative stress likely caused by the triplication of genes such as SOD1. To determine if the abnormal redox state was a factor in the failure of NMDAR-mediated migration in Ts16, we treated Ts16 neurons with either n-acetyl cysteine (NAC) or dithiothrietol (DTT), known antioxidants. The reduction in NMDAR-mediated migration observed in Ts16 neurons was returned to normal littermate values by NAC or DTT. Our data indicate that oxidative stress may play a key role in the abnormal glutamate-mediated responses during cortical development in the Ts16 mouse and may have an impact on neuronal migration at critical stages.

Acetylcysteine↗
PubMedDate not supplied

Perinatal manganese exposure: behavioral, neurochemical, and histopathological effects in the rat.

Manganese chloride (Mn) was dissolved in the drinking water (0, 2, or 10 mg/ml) of dams and their litters from conception until postnatal day (PND) 30. Parturition was uneventful in the Mn-exposed rats and no physical abnormalities were observed. The rats exposed to 10 mg/ml Mn showed a 2.5-fold increase in cortical Mn levels. Their weight gain was attenuated from PND 9-24 and they were hyperactive at PND 17. Neither the 2 nor the 10 mg/ml Mn-exposed groups differed from the controls on the elevated plus apparatus or on the Morris water maze and the radial arm maze. Brain monoamine levels and choline acetyltransferase activity were affected. Tyrosine hydroxylase immunohistochemistry showed that dopamine cells of the substantia nigra were intact. Glial fibrillary acidic protein immunoreactivity was not increased in cortex, caudate, and hippocampus. However, both the low- and high-dose Mn-exposed groups showing thinning of the cerebral cortex. This could have resulted from perinatal malnutrition or from a direct effect of Mn on cortical development.

Analysis of Variance↗
PubMed1999

Cellular and molecular guidance of GABAergic neuronal migration from an extracortical origin to the neocortex.

Formation of the normal mammalian cerebral cortex requires the migration of GABAergic inhibitory interneurons from an extracortical origin, the lateral ganglionic eminence (LGE). Mechanisms guiding the migratory direction of these neurons, or other neurons in the neocortex, are not well understood. We have used an explant assay to study GABAergic neuronal migration and found that the ventricular zone (VZ) of the LGE is repulsive to GABAergic neurons. Furthermore, the secreted protein Slit is a chemorepellent guiding the migratory direction of GABAergic neurons, and blockade of endogenous Slit signaling inhibits the repulsive activity in the VZ. These results have revealed a cellular source of guidance for GABAergic neurons, demonstrated a molecular cue important for cortical development, and suggested a guidance mechanism for the migration of extracortical neurons into the neocortex.

Animals↗
PubMed2001

Tbr1 regulates differentiation of the preplate and layer 6.

During corticogenesis, early-born neurons of the preplate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development.

Animals↗
PubMed1998

In utero irradiation of rats as a model of human cerebrocortical dysgenesis: a review.

Certain developmental abnormalities of the cerebral cortex are closely associated with epilepsy in humans. Exposure of fetal rats to external gamma-irradiation produces diffuse cortical dysplasia and neuronal heterotopia. These abnormalities are the result of radiation-induced cell death coupled with continued cortical development in an altered cellular environment. In vivo electroencephalography studies in these animals have revealed an increased propensity for electrographic seizures in the presence of the sedating agents, acepromazine and xylazine. In vitro neocortical slices containing dysplastic cortex demonstrate enhanced excitability, as compared to control neocortex, when inhibition that is mediated by the A-type gamma-amino butyric acid receptor is blocked with bicuculline methiodide. In utero irradiation of rats produces structural changes that mimic some aspects of cerebral dysgenesis in humans and results in physiologic changes that increase the animals' propensity for seizures. Similarities and differences between the animal model and the human syndromes are discussed.

Animals↗
PubMed1999

The significance of bilateral EEG abnormalities before and after hemispherectomy in children with unilateral major hemisphere lesions.

The rate of seizure relief following hemispherectomy varies between 50 and more than 80%. There has been particular debate concerning the significance of bilateral electroencephalography (EEG) abnormalities in influencing prognosis. This study was set out to determine the frequency of bilateral EEG abnormalities and their relationship to underlying pathology and outcome. We investigated 28 children with unilateral hemisphere lesions, who underwent hemispherectomy. Interictal and ictal EEGs before and after hemispherectomy were reviewed. Post-operative outcome with respect to seizures was noted. Bilateral EEG abnormalities were seen in 75%, but were more common in children with malformations of cortical development than in patients with acquired cerebral lesions, and were found more often in interictal than in ictal records. Post-operative EEG abnormalities were variable and did not consistently predict outcome. Short-term outcome was similar, irrespective of aetiology. With longer term follow-up, only 47% of children with developmental abnormalities were still seizure-free in contrast to 77% of children with acquired abnormalities. Although the incidence of bilateral EEG abnormalities in patients with major unilateral hemisphere lesions is high, these findings alone should not preclude further consideration for hemispherectomy. Our findings emphasise that the aetiology of the lesion plays a major role in determining outcome.

Adolescent↗
PubMed2002

An investigation of the Wnt-signalling pathway in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder.

The Wnt-signalling pathway has been implicated in a variety of processes including cortical development and plasticity. We have previously demonstrated a reduction in glycogen synthase kinase-3beta (GSK-3beta) levels in the prefrontal cortex in schizophrenia and aimed to further elucidate the abnormalities of the Wnt-signalling pathway in this and other psychiatric disorders. Immunoblotting was performed to quantify the levels of three members of the Wnt-signalling pathway, GSK-3beta, beta-catenin and dishevelled-2 (Dvl-2), in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder and in matched controls. We found no significant differences between the disease and control groups for any of the proteins studied, and therefore, cannot confirm our earlier findings of abnormalities of GSK-3beta in schizophrenia.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Developmental insanity or dementia praecox: was the wrong concept adopted?

Over a century ago, the Scottish psychiatrist Thomas Clouston proposed the idea of a developmental or adolescent insanity. He characterised the condition as having a male predominance and a poor outcome, and noted the frequency of a family history and of minor anomalies of the palate; he considered it a disorder of cortical development and the onset of psychotic symptoms due to maturation during adolescence "of certain parts of the brain which had lain dormant before". Clouston's idea was subsequently eclipsed by the broader dementia-praecox espoused by Kraepelin and Bleuler, but recent epidemiological, neuroimaging, and neuropathological research supports the existence, within the schizophrenia syndrome of a group of patients with a severe, early onset, developmental psychosis. This disorder, re-christened as neurodevelopmental schizophrenia, is associated with childhood language and speech difficulties which render subjects more likely to later misinterpret their own inner speech as external voices; like all developmental disorders of language, it is commoner in males. Predisposing factors include the inheritance of abnormal cerebral asymmetry, and early environmental hazards of brain development such as prenatal exposure to maternal viral infection and perinatal complications.

Adolescent↗
PubMed1997

The human striatum in schizophrenia. II. Increased number of striatal neurons in schizophrenics.

In neuropathological studies of schizophrenia, alterations of the basal ganglia are one main topic. Using the optical dissector, we performed an unbiased estimation of neurons and glia cells in the human striatum. To rule out an influence of age and gender, the brains of 9 male schizophrenic patients younger than 65 were closely matched in age with the brains of 9 male control persons. Absolute neuron numbers of the striatum and its subdivisions putamen and nucleus caudatus/nucleus accumbens of both hemispheres were compared between both groups, as were absolute glia cell numbers and the calculated glia index. We found a significant increase in absolute striatal neuron numbers in the schizophrenic group on the right side (P = 0.008**) and only a trend to higher absolute striatal neuron numbers on the left side. In a further analysis, the significant increase of absolute striatal neuron numbers in the right striatum of the schizophrenic group was only discernible for the nucleus caudatus/nucleus accumbens complex (P = 0.01*) and not for the putamen. Absolute striatal glia cell numbers did not differ significantly between both groups, neither on the right nor on the left side. There was only a trend towards a smaller glia index on both sides. Cortical development disturbances with a consecutive reduction of naturally occurring cell death during development could be responsible for this increase in absolute striatal neuron numbers in schizophrenics.

Apoptosis↗
PubMed1998

Brain mapping: Faradization of the mind.

Electromagnetic induction of focal currents in the brain - 'transcranial magnetic stimulation' - can be used to study cortical development and plasticity, as well as the organization of sensory and cognitive functions. It may also prove to be useful tool in the treatment of depression.

Animals↗
PubMed2003

Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex.

Individuals affected with tuberous sclerosis complex (TSC) develop cortical tubers characterized by disorganized cytoarchitecture and morphologically abnormal cell types, such as dysplastic neurons (DNs) and giant cells (GCs). As part of ongoing cDNA array analysis to study the molecular pathogenesis of tuber formation, we detected increased expression of intercellular adhesion molecule-1 (ICAM-1) mRNA, a cell adhesion molecule (CAM) that functions in cytokine signaling, in tubers. Western and immunohistochemical analyses revealed that ICAM-1 protein was selectively expressed in tubers, but was only minimally expressed in control cortex, adjacent nontuberal cortex, or in non-TSC focal cortical dysplasia. Increased expression of ICAM-1 was found in mice in which the Tsc1 gene was conditionally inactivated in astrocytes. Expression of molecules involved in ICAM-1 activation and cytokine signaling were increased in tubers, including tumor necrosis factor alpha (TNF-alpha), mitogen activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB). Numerous CD68-immunoreactive macrophages were observed clustered around GCs further supporting an inflammatory response in tubers. Expression of caspase 8 and Fas support cytokine activation and detection of TUNEL reactivity suggests ongoing cell death in tubers. Specific alterations in ICAM-1, TNF-alpha, NF-kappaB1, and MAPK expression coupled with the detection of numerous CD68-immunoreactive macrophages suggests activation of proinflammatory cytokine signaling pathways in tubers that may culminate in cell death.

Adult↗
PubMed1995

Wiring, dysmorphogenesis and epilepsy: a hypothesis.

Cerebral cortical dysgenesis has been found by magnetic resonance imaging to be the second most common pathology underlying medically refractory chronic partial epilepsy. Patients with the latter condition form the largest group in specialist epilepsy clinics. The pathogenesis of the epilepsy in cortical dysgenesis remains largely obscure. The most popular current hypothesis holds neuronal misconnection secondary to neuronal malpositioning culpable for seizure activity. However, a review of the published literature of cortical dysgenesis and an analysis of newer magnetic resonance and histopathological data, suggests that this view is no longer tenable. A modified hypothesis is proposed in which neuronal connectivity itself is postulated to be the primary motive force in both cerebral morphogenesis and epileptogenesis in cases of cortical dysgenesis. This hypothesis leads to the generation of a model for cortical development and directly testable predictions of intercellular connectivity, as well as a potential tool for the prediction of the possibility of freedom from seizure activity after surgical resection of dysgenetic lesions in individual cases.

Animals↗
PubMed1998

Dysversion of the optic disc and axial length measurements in a presumed amblyopic population.

PURPOSE: Our purpose was to evaluate anatomic variations of eyes presumed to be amblyopic. METHOD: Computer imaging and photography of the optic discs of 205 amblyopic subjects were performed and the axial lengths of 183 of the subjects were measured. The paired optic nerve images were evaluated for symmetry of disc contours and orientation of central blood vessels to detect optic nerve head dysversion. Dysversion of the optic nerve head, which is also referred to as segmental hypoplasia, is a congenital disorder characterized by the central retinal vessels emerging temporal to the vertical midline of the disc and being directed nasally or the nerve head tilting in a vertical direction resulting in a downward or oblique tilting of the discs with the blood vessels emerging at the superior or inferior disc rim. RESULTS: Ninety-three subjects had optic nerve dysversion. There was a greater degree of anisometropia (P< or =.004) in subjects with dysversion (anisometropia factor of 2.51+/-2.15) than in the subjects with symmetric discs (anisometropia factor of 1.76+/-1.63). Axial lengths of the amblyopic eyes were significantly smaller (P<.0001) than those of the nonamblyopic eyes. There was no statistical difference (P< or =.879) in length between amblyopic eyes with dysversion and those with symmetric discs. CONCLUSION: Optic disc dysversion was identified in 45.4% of patients who were previously assumed to be amblyopic. There are anatomic malformations in the eyes of a significant proportion of the presumed amblyopic population. This suggests that, in these individuals, congenital peripheral factors rather than impaired cortical development may be responsible for decreased unilateral acuity.

Adolescent↗
PubMed2000

Lissencephaly and subcortical band heterotopia: molecular basis and diagnosis.

Magnetic resonance imaging is now used routinely in the evaluation of developmental and neurological disorders and provides exquisite images of the living human brain. Consequently, it is evident that cortical malformations are more common than previously thought. Among the most severe is classical lissencephaly, in which the cortex lacks the complex folding that characterizes the normal human brain. Lissencephaly includes agyria and pachygyria, and merges with subcortical band heterotopia. Current molecular genetic techniques combined with the identification of affected patients have enabled the detection of two of the genes responsible: LIS1 (PAFAH1B1) on chromosome 17 and DCX (doublecortin) on the X chromosome. This review highlights the discovery of these genes and discusses the advances made in understanding the molecular basis of cortical development and improvements in diagnosis and genetic counseling.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

Single cause, polymorphic neuronal migration disorders: an animal model.

Injury to the developing cortical plate can result in a variety of neuronal migration disorders. The results are reported of experimental research aimed at determining whether these different types of neocortical malformations are the consequence of comparable injury of varying intensity. Freezing probes were placed on the skulls of 44 newborn rats (age equivalent to 4 to 5 months of gestation in humans) and induced either one or two freezing injuries of durations ranging from 2 to 20 seconds. A variety of cortical malformations including minor laminar dysplasias, molecular layer ectopias, microgyria, and porencephalic cysts were seen in the brains of these animals when they were examined on postnatal day (P)2, P21, and P60. The severity of the malformation was directly related to the strength (number of hits and duration) of the freezing injury. These results suggest that a single etiologic event of varying severity during neuronal migration to the neocortex can induce widely disparate malformations of the cortex.

Animals↗
PubMed2002

Effect of propionic and methylmalonic acids on the high molecular weight neurofilament subunit (NF-H) in rat cerebral cortex.

Propionic and methylmalonic acidemias are inherited neurometabolic disorders biochemically characterized by tissue accumulation of propionic (PA) and methylmalonic (MMA) acids, respectively. Neurofilaments (NF) are important cytoskeletal proteins and phosphorylation/dephosphorylation of NF is important to stabilize the cytoskeleton. We investigated the effects of PA and MMA on the high molecular weight neurofilament subunit associated with the cytoskeletal fraction of rat cerebral cortex along development. Cortical slices from 9- to 60-day-old rats were incubated with 2.5 mM PA or MMA. The cytoskeletal fraction was extracted and the immunoreactivity for phosphorylated or total NF-H was analyzed by immunoblotting using specific antibodies. Results showed that treatment of tissue slices with the acids induced an increased Triton-insoluble phosphorylated NF-H immunoreactivity in up to 17-day-old rats. Furthermore, treatments significantly increased the total amount of NF-H in 12-day-old rats. These findings indicate that PA and MMA alter the dynamic regulation of NF-H assembly in the cytoskeletal fraction.

Animals↗
PubMed2000

Neuronal migration defects of the cerebral cortex: a destination debacle.

Disruptions in neuronal migration have been postulated as the basis for many cerebral malformations including lissencephaly, cortical heterotopia, and double cortex. Recently, the genetic basis for some of these disorders has been identified. In this review, we highlight recent advances in our understanding of the molecular mechanisms of neuronal migration and its relationship to cerebral cortical development and neuronal migration disorders. This has allowed us to begin categorizing specific malformations based on their molecular etiology.

Animals↗
PubMed2000

Nuclear Notch1 signaling and the regulation of dendritic development.

To understand the function of Notch in the mammalian brain, we examined Notch1 signaling and its cellular consequences in developing cortical neurons. We found that the cytoplasmic domain of endogenous Notch1 translocated to the nucleus during neuronal differentiation. Notch1 cytoplasmic-domain constructs transfected into cortical neurons were present in multiple phosphorylated forms, localized to the nucleus and could induce CBF1-mediated transactivation. Molecular perturbation experiments suggested that Notch1 signaling in cortical neurons promoted dendritic branching and inhibited dendritic growth. These observations show that Notch1 signaling to the nucleus exerts an important regulatory influence on the specification of dendritic morphology in neurons.

Animals↗