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Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analyzed surgical tissue from 25 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR or amplicon sequencing, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 64% (n = 16/25) of cases. Of these, five cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n = 3) or DEPDC5 (n = 2). Somatic variants were identified in 44% (n = 11/25) of cases. The genetic yield for FCDIIb was 77% of cases having a pathogenic mTOR pathway variant detected (n = 10/13), and for FCDIIa 66% (n = 6/9). High depth sequencing approaches allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 62% (n = 15/24) of the cases with ≥12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n = 9 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treatments.

Humans↗

Early generation of glia in the intermediate zone of the developing cerebral cortex.

Radial glia are present at the earliest stage of cerebral cortical development, and later they transform into astrocytes. Other glial cells including astrocytes and oligodendrocytes are thought to appear only after neuron generation is complete and the cortical layers are formed. Little is known of when and where microglia enter the central nervous system and proliferate. We addressed the question of the origin of these three glial cell types in the developing ferret cerebral cortex. We assessed the temporal pattern of glial cell division by administering [3H]thymidine to label cells in S phase, and by using survival periods of 1-2 h to label dividing cells in situ. Labeled cells were identified in the developing intermediate zone of the ferret cerebral wall. These cells were present at E28, and reached a maximum number at P1. Double labeling experiments identified these cells as astrocytes, oligodendrocytes or microglia. None of the dividing cells expressed neuronal markers. These data show that all three types of glia are generated in the developing subcortical white matter, and that glial progenitors are present in the intermediate zone as soon as it becomes a recognizable structure. These data also show that the period of glial generation overlaps extensively with the period of neuron generation, since neuron generation is not complete until the end of the second postnatal week in the ferret.

Animals↗

Cortical malformations and epilepsy: new insights from animal models.

In the last decade, the recognition of the high frequency of cortical malformations among patients with epilepsy especially children, has led to a renewed interest in the study of the pathophysiology of cortical development. This field has also been spurred by the recent development of several experimental genetic and non-genetic, primarily rodent, models of cortical malformations. Epileptiform activity in these animals can appear as spontaneous seizure activity in vivo, in vitro hyperexcitability, or reduced seizure susceptibility in vitro and in vivo. In the neonatal freeze lesion model, that mimics human microgyria, hyperexcitability is caused by a reorganization of the network in the borders of the malformation. In the prenatal methylazoxymethanol model, that causes a diffuse cortical malformation, hyperexcitability is associated with alteration of firing properties of discrete neuronal subpopulations together with the formation of bridges between normally unconnected structures. In agreement with clinical evidence, these experimental data suggest that cortical malformations can both form epileptogenic foci and alter brain development in a manner that causes a diffuse hyperexcitability of the cortical network.

Abnormalities, Drug-Induced↗

Maternally derived immunoglobulin light chain is present in the fetal mammalian CNS.

Toward identifying molecules involved in cell-cell interactions during cerebral cortical development, we have investigated the nature of immunoglobulin-like immunoreactivity (Ig-ir) in the murine cortex. Immunohistochemistry using several antisera recognizing IgG revealed intense immunoreactivity in the subplate and marginal zone of embryonic day 16 cortex, as well as in the hindbrain and spinal cord, particularly within ventral fiber tracts. In three independently derived mouse strains lacking the recombination activating genes RAG-1 or RAG-2, which are essential for Ig production, Ig-ir was absent from the fetal CNS. Western blot analyses of wild-type brains from embryonic day 12 through birth identified a 25 kDa protein that co-migrated with Ig light chain and was absent from RAG-1 or RAG-2 -/- brain samples. This result could be replicated with an antiserum specific for Ig kappa light chain, but not with antisera specific for Ig gamma or mu heavy chain. No Ig-ir was detected in the brains of RAG-1 +/- embryos carried by a -/- female, suggesting a maternal source of the immunoreactive molecule. In confirmation of this, Ig-ir could be partially reproduced by intraperitoneal injection of pregnant RAG-1 -/- females with normal mouse serum. We conclude that maternally derived Ig light chain is present in the fetal murine CNS. This may represent a novel maternal contribution to fetal neural development and implicates Ig molecules as potential mediators of cortical developmental events.

Animals↗

Glutamate acting at NMDA receptors stimulates embryonic cortical neuronal migration.

During cortical development, embryonic neurons migrate from germinal zones near the ventricle into the cortical plate, where they organize into layers. Mechanisms that direct neuronal migration may include molecules that act as chemoattractants. In rats, GABA, which localizes near the target destination for migrating cortical neurons, stimulates embryonic neuronal migration in vitro. In mice, glutamate is highly localized near the target destinations for migrating cortical neurons. Glutamate-induced migration of murine embryonic cortical cells was evaluated in cell dissociates and cortical slice cultures. In dissociates, the chemotropic effects of glutamate were 10-fold greater than the effects of GABA, demonstrating that for murine cortical cells, glutamate is a more potent chemoattractant than GABA. Thus, cortical chemoattractants appear to differ between species. Micromolar glutamate stimulated neuronal chemotaxis that was mimicked by microM NMDA but not by other ionotropic glutamate receptor agonists (AMPA, kainate, quisqualate). Responding cells were primarily derived from immature cortical regions [ventricular zone (vz)/subventricular zone (svz)]. Bromodeoxyuridine (BrdU) pulse labeling of cortical slices cultured in NMDA antagonists (microM MK801 or APV) revealed that antagonist exposure blocked the migration of BrdU-positive cells from the vz/svz into the cortical plate. PCR confirmed the presence of NMDA receptor expression in vz/svz cells, whereas electrophysiology and Ca2+ imaging demonstrated that vz/svz cells exhibited physiological responses to NMDA. These studies indicate that, in mice, glutamate may serve as a chemoattractant for neurons in the developing cortex, signaling cells to migrate into the cortical plate via NMDA receptor activation.

Animals↗

Development of projections from somatic motor-sensory areas of neocortex to the diencephalon and brainstem in the North American opossum.

The development of projections from somatic motor-sensory areas of neocortex to the diencephalon and brainstem was studied by using the orthograde transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) in a series of pouch-young opossums. The opossum was chosen for study because it is born in a very immature state, 12 days after conception, and has a protracted postnatal development. Cortical axons form a cerebral peduncle by at least postnatal day (PD) 10, a medullary pyramid by estimated PD (EPD) 17, a pyramidal decussation by EPD 26, and reach the first cervical segment of the spinal cord by EPD 29. Cortical axons innervate diencephalic nuclei and perhaps the substantia nigra by EPD 17, but do not grow into more caudal brainstem nuclei until EPD 26. The first brainstem areas innervated by cortical axons are the mesencephalic and rostral pontine tegmentum and parts of the pontine gray adjacent to the pyramidal tract (EPD 29). By EPD 31, cortical axons project to additional areas of the pontine gray, the gigantocellular reticular formation, the medial accessory olive, and the cuneate nucleus. Cortical innervation of the red nucleus and superior colliculus begins at EPD 31 but is not well developed until EPD 35. Cortical axons do not innervate the parvicellular reticular formation or the sensory trigeminal nuclei until EPD 35. Evidence for transient cerebrocerebellar axons was also found.

Animals↗

[Prenatal development and postnatal changes in the guinea pig cortex: microscopic evaluation of a natural deprivation experiment. I. Prenatal development].

The present paper is based on the question, to what extent the cortical structure is determined by genetic factors and how far it is dependent on environmental stimuli. Some deprivation experiment in the literature have supported the assumption tha excitation coming from the sense organs contributes to the formation of synaptic connections in the cortex. This made it possible to invoke the formation of synapses (or dendritic spines) as a substrate of learning processes. Results of experiments on the influence of artificial environments on the formation of synapses have been, however, somewhat contradictory. On this background it was interesting to investigate the cortical development of the guinea-pig, an animal which is highly developed at birth. This percocity separates in time the process of genetically determined development from the changes due to environmental stimuli, which are amply overlapping in altricial animals such as mouse, rat, and cat. A comparison between the cortices of prenatal and adult guinea-pigs showed that the density of dendritic spines has reached adult values already before birth (12/10 micrometers dendritic length before birth, 11,5/10 micrometers in adult animals, fig. 5-8, and 17). The counts have been made on basal dendrites of Golgi-impregnated pyramidal cells in the upper third of the cortex. Also, the difference in the density of synapses on electronmicrographs in animals just before birth (8,9 x 10(8)/mm(3)) and in adult animals (9,4 x 10(8)/mm(3)) was not significant (figs. 13, 14, and 16). The samples have been taken from the second cortical layer. The two areas investigated showed small but significant differences in the time course of spine formation. In both areas the density of spines reached a maximum first and then decreased slightly toward the adult values. However, in the postcallosal area the maximum was reached earlier than in the precallosal area (fig. 9). The decrease in spine density after the maximum, about 18% in both areas, may be partly explained by the growth of dendrites. From the increase in brain volume between birth and adult age and from the density of synapses at different stages, one can conclude that the total number of synapses at birth is about two thirds of that in adult animals. Similarly, the proportion of spines present at birth was at least the same or even higher (fig. 12). Thus, most of the connections in the cortex of the guniea pig are formed without the influence of environmental stimuli. This puts strong doubts on the idea of the formation of synapses or dendritic spines as memory traces. Synapses and spines seem to be the prerequisites of learning rather than the result of it. In part II the question will be examined, if postnatal changes in the cortex of the guinea-pig, especially on spines and synapses, are possible candidates for memory traces.

Animals↗

Changes in density of brainstem afferents in ferret primary auditory cortex (AI) during postnatal development.

Histochemical methods were used to assess the distribution of 4 neurotransmitters thought to be involved in cortical plasticity. They were measured in the primary auditory cortex of the ferret from just before the onset of hearing. Acetylcholinesterase staining was strongest in layers I, IV and VI and there was a gradual increase in the amount of staining from postnatal day (PND) 21 through to adulthood. Serotonin fibres were located mainly in layers I-III and their density increased gradually over the same time period. Noradrenergic fibres were sparsely scattered throughout the cortex but their density and distribution showed little change over the age range studied. Dopaminergic fibres were densest in layers V and VI at all ages. However, there was a transient doubling in their density that started round about the onset of hearing at PND 28, peaked at PND 35 and had returned to baseline levels by 2 wk later. This transient peak in density did not occur in the adjacent suprasylvian gyrus and did not appear to be a general phenomenon. The local transient increase in dopaminergic fibres implies that they may have an important role during a short period in auditory cortical development. This role may involve modifying the cortical circuitry that is involved in analysing the input from the auditory periphery.

Acetylcholinesterase↗

Wnt receptors and Wnt inhibitors are expressed in gradients in the developing telencephalon.

The caudomedial margin of the medial pallium, known as the cortical hem, expresses several Wnt genes that have been shown to be crucial for cortical development. We examined the expression of members of the Frizzled (mFz) family of Wnt receptors and the Secreted Frizzled Related Protein (SFRP) family of Wnt inhibitors during telencephalic development. We found that mFz-5 and mFz-8 are specifically expressed in the neocortical neuroepithelium and excluded from the hippocampal neuroepithelium in early telencephalic development, whereas mFz-9 and mFz-10 have expression domains confined to the medial pallium. In addition, SFRP-1 and SFRP-3 are expressed in opposing anterolateral to caudomedial gradients within the telencephalic ventricular zone throughout corticogenesis.

Animals↗

[Cortical blindness during treatment with cyclosporin].

A 40-year-old man developed cortical blindness during cyclosporin treatment shortly after an allogeneic bone marrow transplantation for chronic myeloid leukaemia. At that time the patient had a therapeutic cyclosporin blood level (226 ng/ml), but a low serum magnesium level and a marginally decreased serum cholesterol level. In addition the patient had hypertension, headache and paraesthesia in the oral, palmar and plantar areas. Vision was fully recovered after discontinuation of the cyclosporin treatment and correction of the hypomagnesaemia. Eighteen cases of cortical blindness during cyclosporin treatment are now known in the literature. Hypomagnesaemia appears to be implicated in the pathogenesis.

Adult↗

Tonic activity of metabotropic glutamate receptors is involved in developmental modification of short-term plasticity in the neocortex.

Maturation of many synapses of the CNS is characterized by a reduction in initial release probability and associated alterations in short-term plasticity (STP). We investigated the role of tonic activity of metabotropic glutamate receptors (mGluRs) in this process in glutamatergic synapses of rat neocortex. Consistent with previous reports, STP of excitatory postsynaptic currents (EPSCs) evoked by five-pulse stimulation was found to switch from depression at postnatal days 13-17 (P13-17) to facilitation at postnatal days 28-42 (P28-42). (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine, a specific mGluR2/3 agonist, strongly depressed EPSCs both at the early stage and the late stage of cortical development. This was accompanied by a switch from depression to facilitation of STP at the early stage and an increase in facilitation at the late stage. While application of 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl) propanoic acid (LY341495), an mGluR antagonist that is most potent at mGluR2/3, had no significant effect at the early stage, it significantly enhanced EPSC amplitude and reduced short-term facilitation at the late stage. Blocking glutamate transporter activity with l-trans-pyrrolidine-2,4-dicarboxylate (tPDC) significantly reduced EPSC amplitude and short-term depression in the younger group but had no effect in the older specimens. The effect of tPDC was blocked by LY341495. These results suggest that a progressive increase in tonic mGluR activity during postnatal development contributes to a reduction of release probability in excitatory cortical synapses. They also indicate that glutamate transporter activity in the neocortex decreases during postnatal development. This may play a role in increasing tonic activity of mGluRs by increasing ambient glutamate levels in the perisynaptic extracellular space.

Aging↗

Morphological differentiation of distinct neuronal classes in embryonic turtle cerebral cortex.

As a starting point for understanding the development of the cerebral cortex in reptiles and for determining how reptilian cortical development compares to that in other vertebrate classes, we studied the appearance and morphological differentiation of cerebral cortical neurons in embryonic turtles. 3H-thymidine birthdate labeling and focal injections of horseradish peroxidase (HRP) in in vitro cortical slices revealed that replicating cells occupy the outer ventricular zone, and subsequently migrate to the ventricular surface where they divide. Postmitotic neurons begin differentiating and elaborating neurites while migrating back through the ventricular zone. On their arrival at the top of the ventricular zone, pyramidal and nonpyramidal neurons can be distinguished morphologically. Cells with multipolar apical dendritic tufts ascending in the marginal zone resemble immature pyramidal neurons. Neurons morphologically similar to these early pyramidal cells were retrogradely labeled by injections of the lipophilic tracer 1,1-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (diI) in a known pyramidal cell target, the thalamus. Nonpyramidal neurons, resembling Cajal-Retzius cells, had horizontally oriented long axons and dendrites coursing in the plexiform primordium, the future marginal zone. With further development morphological differences between cell types became accentuated, and pyramidal cell somata were segregated into a single cellular layer flanked by zones containing predominantly nonpyramidal cells. Axon elaboration occurred early in embryonic development, as pyramidal cells sent axonal branches to the septum, thalamus, and cortical targets soon after their generation, and the intracortical axonal plexus became increasingly dense during embryonic life. Over a similar time course the distribution of projecting neurons labeled by thalamic diI injections changed from an initial homogeneous distribution to a preferential location in the superficial half of the cellular layer. Results from this study demonstrate several features of cortical differentiation that are conserved in reptiles and mammals, including similar early morphological differentiation events, the early distinction of principal cell types, and the parallel development of pyramidal and nonpyramidal neurons. The context in which these similar developmental events occur, however, differs profoundly in reptiles and mammals, with differences in the timing and location of neurite elaboration and differences in the appearance and architectonic organization of the cortex. Comparison of cortical developmental patterns between reptiles and mammals shows that similar functional cortical circuits with balanced excitation and inhibition can emerge in diverse cortical structures.

Animals↗

Embryonic and early postnatal abnormalities contributing to the development of hippocampal malformations in a rodent model of dysplasia.

While there are many recent examples of single gene deletions that lead to defects in cortical development, most human cases of cortical disorganization can be attributed to a combination of environmental and genetic factors. Elucidating the cellular or developmental basis of teratogenic exposures in experimental animals is an important approach to understanding how environmental insults at particular developmental junctures can lead to complex brain malformations. Rats with prenatal exposure to methylazoxymethanol (MAM) reproduce many anatomical features seen in epilepsy patients. Previous studies have shown that heterotopic clusters of neocortically derived neurons exhibit hyperexcitable firing activity and may be a source of heightened seizure susceptibility; however, the events that lead to the formation of these abnormal cell clusters is unclear. Here we used a panel of molecular markers and birthdating studies to show that in MAM-exposed rats the abnormal cell clusters (heterotopia) first appear postnatally in the hippocampus (P1-2) and that their appearance is preceded by a distinct sequence of perturbations in neocortical development: 1) disruption of the radial glial scaffolding with premature astroglial differentiation, and 2) thickening of the marginal zone with redistribution of Cajal-Retzius neurons to deeper layers. These initial events are followed by disruption of the cortical plate and appearance of subventricular zone nodules. Finally, we observed the erosion of neocortical subventricular zone nodules into the hippocampus around parturition followed by migration of nodules to hippocampus. We conclude that prenatal MAM exposure disrupts critical developmental processes and prenatal neocortical structures, ultimately resulting in neocortical disorganization and hippocampal malformations.

Animals↗

Differential expression of K4-AP currents and Kv3.1 potassium channel transcripts in cortical neurons that develop distinct firing phenotypes.

Maturation of electrical excitability during early postnatal development is critical to formation of functional neural circuitry in the mammalian neocortex. Little is known, however, about the changes in gene expression underlying the development of firing properties that characterize different classes of cortical neurons. Here we describe the development of cortical neurons with two distinct firing phenotypes, regular-spiking (RS) and fast-spiking (FS), that appear to emerge from a population of immature multiple-spiking (IMS) neurons during the first two postnatal weeks, both in vivo (within layer IV) and in vitro. We report the expression of a slowly inactivating, 4-AP-sensitive potassium current (K4-AP) at significantly higher density in FS compared with RS neurons. The same current is expressed at intermediate levels in IMS neurons. The kinetic, voltage-dependent, and pharmacological properties of the K4-AP current are similar to those observed by heterologous expression of Kv3.1 potassium channel mRNA. Single-cell RT-PCR analysis demonstrates that PCR products representing Kv3.1 transcripts are amplified more frequently from FS than RS neurons, with an intermediate frequency of Kv3.1 detection in neurons with immature firing properties. Taken together, these data suggest that the Kv3.1 gene encodes the K4-AP current and that expression of this gene is regulated in a cell-specific manner during development. Analysis of the effects of 4-AP on firing properties suggests that the K4-AP current is important for rapid action potential repolarization, fast after-hyperpolarization, brief refractory period, and high firing frequency characteristic of FS GABAergic interneurons.

Action Potentials↗

Cortical dysplasias and epilepsy: a review of the architectonic, clinical, and seizure patterns.

Since the nineteenth century, various abnormalities of cortical development resulting from migration defect, disorders of maturation, and disorders of cortical organization were described in brains at autopsy. Cortical dysplasia then was recognized in tissue resected during surgical treatment of patients with intractable epilepsy, but this finding remained largely unappreciated until the development of modern imaging. CT allowed glimpses of the more obvious malformations, but it was the advent of MRI that enabled the recognition and classification of the different types of lesions. In the Taylor type of cortical dysplasia, it became clear that there was a wide range in the severity and, above all, in the extent of the abnormality. The lesions range from small areas, often difficult to identify, to extensive lesions surrounded by a halo or penumbra of presumably less severe, but still clinically significant, structural abnormality. Functional imaging (SPECT, PET, and MRS) have provided additional insights and led to strategies for surgical treatment. Even lesions involving the central strip may at times be successfully resected, but in such patients much depends on the preoperative neurologic status. Recognition of the fact that dysplastic lesions are in themselves epileptogenic has been another milestone in our understanding of these abnormalities. Subcortical heterotopias, in particular periventricular nodular heterotopias, have been recognized as causing intractable epilepsy in some but not in all patients. Surgical approaches to these lesions are now being planned. The hereditary nature of the lesions in some patients has explained the familial occurrence of epilepsy in a number of instances. Generalized epileptic abnormalities and generalized disorders of migration and maturation have been described as band heterotopia or the double-cortex syndrome. Here, too, sex-linked dominant inheritance may occur, and progress has been made in our understanding of the mechanisms of these genetically determined lesions. Focal resection in patients with band heterotopia, however, has been of little value in the small number of patients in whom it has been carried out. Cortical malformations due to disorganization, occurring later in intrauterine life, are represented by micropolygyria. These lesions are often bilateral and perisylvian, but at times they are unilateral and in some patients may be occipital or frontal. Several syndromes have emerged, the most common being the one characterized by severe pseudobulbar palsy and mild pyramidal deficit (31). In some patients with such cortical abnormalities, particularly those with micropolygyria, the epilepsy may not be intractable, and full control may be obtained by medical treatment (32). Interesting and important clinical features of patients with bilateral perisylvian polymicrogyria were described by Guerrini et al. (33) and Caraballo et al. (34). In some patients who develop a secondary generalized electrographic abnormality and drop attacks early in the first decade, there is eventual improvement and cessation of the epileptic abnormality toward the end of the first decade or somewhat later. These investigators stressed that callosotomy should be considered with caution in patients with micropolygyria and this electroclinical pattern. Hypothalamic hamartomata and the associated epileptic syndrome have been better understood in recent years. Despite the risks of surgery, resection of the lesion offers hope of improvement in seizure control and of the often extremely severe behavioral abnormalities. On the other hand, patients with small lesions leading only to a "need to laugh" without more overt epileptic or behavioral manifestations are now being recognized. Finally, initial investigations have begun to uncover the transmitter abnormalities in patients with cortical dysplasia. (ABSTRACT TRUNCATED)

Brain↗

DCAMKL1, a brain-specific transmembrane protein on 13q12.3 that is similar to doublecortin (DCX).

Mutations in the human doublecortin (DCX), a brain-specific putative signaling protein, cause X-linked lissencephaly and subcortical band heterotopia. A predicted 740-amino-acid protein from human brain has two distinct regions, an N-terminal 345-amino-acid region 78% similar to the DCX protein and a C-terminal 427-amino-acid region that contains two transmembrane domains and is 98% homologous to a rat Ca2+/calmodulin-dependent protein kinase. We have designated this protein DCAMKL1. It maps to chromosome 13q12.3-q13, within a 540-kb YAC clone containing markers D13S805 and D13S1164. Northern analysis detected three major transcript isoforms of the DCAMKL1 gene expressed differentially and predominantly in human fetal and adult brain and during mouse embryogenesis (11-17 dpc). These results and its homology with the DCX and Ca2+/calmodulin dependent kinase proteins suggest a likely role for DCAMKL1 transmembrane protein in developing and adult brain, possibly in a pathway of cortical development.

Amino Acid Sequence↗

Developmental changes in cyclooxygenase mRNA expression in the kidney of rats.

Prostaglandins, synthesized by cyclooxygenase (COX), regulate renal hemodynamics and also epithelial water and solute transport. To determine whether COX mRNA expression changes with age, we studied expression in renal medulla and in cortex in developing rats at various ages. We also examined age-related changes in COX mRNA expression induced by lipopolysaccharide (LPS). COX mRNA was quantitatively analyzed in a real-time polymerase chain reaction (PCR) with dual-labeled fluorogenic probes. COX-1 mRNA expression did not change with age in cortex or medulla. COX-2 mRNA expression was highest in 1-week-old rats and lowest in 4- and 8-week-old rats. Lipopolysaccharide treatment did not alter COX-1 mRNA expression in infantile or adult rats. In adults, LPS at 1, 5, and 10 mg/kg induced COX-2 mRNA expression in renal medulla; the higher doses, 5 and 10 mg/kg, induced COX-2 expression in cortex. In infantile rats, COX-2 mRNA, already high in the unmanipulated state, was further increased by only 1 mg/kg LPS in both renal cortex and medulla. Age-related changes in the expression of COX-2 mRNA might be responsible for changing physiologic characteristics of renal function during postnatal development in rats, and may be important in renal cortical development.

Aging↗

Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia.

Cytoarchitectural abnormalities have been reported in the cortex in schizophrenia. These suggest a developmental origin for this disorder. The Wnt signalling pathway is involved in the regulation of brain development; disruption of this pathway may lead to abnormal cortical development. In this study levels of three components of the Wnt signalling pathway; glycogen synthase kinase-3beta(GSK-3beta), beta-catenin and dishevelled-2 (Dvl-2) were determined in the prefrontal cortex of ten schizophrenic and ten control individuals using immunoblotting. GSK-3beta levels were significantly reduced in the schizophrenic group, while levels of beta-catenin and Dvl-2 did not differ between groups. This provides further evidence for an abnormality of the Wnt signalling pathway in schizophrenia.

Adaptor Proteins, Signal Transducing↗