Normal Development Of Central Nervous System Research Articles

Challenges, status, and opportunities for studying developmental neuropathology in adult schizophrenia.

Neurodevelopmental theories of the pathoetiology of schizophrenia have been at the forefront of schizophrenia research in recent years. Support for these theories is substantial and growing. Epidemiological, phenomenological, and clinical neurobiological research have provided compelling though still circumstantial evidence. Neuropathological investigations also have provided some evidence; however, these have yet to actualize their potential for revealing the cellular and molecular nature of developmental aberrancies in this disease. This article summarizes the clinical evidence suggesting abnormal neurodevelopment in schizophrenia, outlines some of the important anatomic, cellular, and molecular mechanisms of normal central nervous system development, reviews current neuropathological findings relevant to neurodevelopment in schizophrenia, and suggests some new directions and opportunities for discovering the molecular neurodevelopmental basis of the disorder.

Regulation of dendritic spine stability

Dendritic spines undergo several types of transformations, ranging from growth to collapse, and from elongation to shortening, and they experience dynamic morphological activity on a rapid time scale. Changes in spine number and morphology occur under pathological conditions like excitotoxicity, but also during normal central nervous system development, during hormonal fluctuations, and in response to neural activity under physiological circumstances. We briefly review evidence for various types of alterations in spines, and discuss the possible molecular basis for changes in spine stability. Filamentous actin appears to be the most important cytoskeletal component of spines, and a growing list of actin-associated and actin-regulatory proteins has been reported to reside within spines. We conclude that spines contain two distinct pools of actin filaments (one stable, the other unstable) that provide the spine with both a stable core structure and a dynamic, complex shape. Finally, we review the current state of knowledge of actin filament regulation, based on studies in nonneuronal cells. Hippocampus 2000;10:542–554. © 2000 Wiley-Liss, Inc.

Regulation of dendritic spine stability.

Dendritic spines undergo several types of transformations, ranging from growth to collapse, and from elongation to shortening, and they experience dynamic morphological activity on a rapid time scale. Changes in spine number and morphology occur under pathological conditions like excitotoxicity, but also during normal central nervous system development, during hormonal fluctuations, and in response to neural activity under physiological circumstances. We briefly review evidence for various types of alterations in spines, and discuss the possible molecular basis for changes in spine stability. Filamentous actin appears to be the most important cytoskeletal component of spines, and a growing list of actin-associated and actin-regulatory proteins has been reported to reside within spines. We conclude that spines contain two distinct pools of actin filaments (one stable, the other unstable) that provide the spine with both a stable core structure and a dynamic, complex shape. Finally, we review the current state of knowledge of actin filament regulation, based on studies in nonneuronal cells.

Chapter 7 Reconstruction of cortical circuitry

Publisher Summary This chapter discusses the ongoing studies of neocortical transplantation for brain repair in their historical context, and provides background for current studies from prior experiments. The chapter describes the ways in which studies using neocortical transplantation have contributed to the understanding of neocortical development. Understanding the factors that control neocortical neuronal development and plasticity is critical to the goal of reconstruction of complex neocortical circuitry in the adult. Toward these ends, as studies of neocortical development proceed, it will be critical to investigate the molecular controls over the growth, survival, differentiation, and plasticity of immature neurons during normal central nervous system (CNS) development and to find ways to harness this information to reconstruct neocortical circuits in the degenerated or damaged adult cerebral cortex. The future possibility of replacing degenerating or injured neurons in the adult neocortex toward functional reconstruction of complex circuitry is also discussed in the chapter.

Characterization of seizures in the flathead rat: a new genetic model of epilepsy in early postnatal development.

Disorders in normal central nervous system (CNS) development are often associated with epilepsy. This report characterizes seizures in a novel genetic model of developmental epilepsy, the Flathead (FH) rat. Animals (n = 76) ages P0-22 were monitored for clinical and electrographic seizure activity. The effects of various AEDs on seizure frequency and duration also were assessed: phenobarbital (PB; 40 mg/kg), valproate (VPA; 400 mg/kg), or ethosuximide (ESM; 600 mg/kg). FHs display episodes of behavior characterized by whole-body tremor, strub tail, alternating forelimb clonus, and complete tonus. EEG recordings from neocortex reveal that FH seizures are bilateral and begin around P7. Seizures occur at a frequency of approximately six per hour from P7 to P18 and the average duration of seizures increases through development. PB, VPA, and ESM failed to prevent seizures; however, PB significantly increased the interval of seizures but had no effects on the duration of seizures, whereas VPA decreased the duration of seizures and not the interval. Seizures in FH rats occur at a constant and high frequency through a defined period in early postnatal development, and these seizures are not completely blocked by high doses of PB, VPA, or ESM. Because FH is a single-locus mutant displaying a highly regular pattern of seizure activity, it is an ideal model for examining the process of epileptogenesis in the developing brain, evaluating new AED therapies, and determining the identity of a gene essential to the normal development of cortical excitability.

Ontogeny of Na+-K+-ATPase in the Brain of Fetal, Neonatal and Adult Sheep † 1098

The sodium pump, Na+-K+-ATPase, is a ubiquitious plasma membrane-bound class of enzymes responsible for Na+ and K+ translocation across cell membranes. Na+-K+-ATPase is essential for the generation of the electrochemical gradients that control the ionic environment necessary for neuronal activity. Therefore, this enzyme is likely to play a critical role in normal central nervous system development. As an initial attempt to examine the importance of this class of enzymes in ovine brain development, we examined the ontogeny of central nervous system Na+-K+-ATPase activity in the cortex of fetuses at 60% or 87 days (n=3), 80% or 120 days (n=6) of gestation, newborn lambs at 5 days of age(n=4) and adult ewes (n=4). Na+-K+-ATPase activity was estimated in crude total membrane preparations by the measurement of ouabain sensitive inorganic phosphate liberation from ATP expressed as mmoles Pi/mg protein/hr. Na+-K+-ATPase activity was 6.61 ± 1.16 (M± SD) at 60% of gestation, 12.56 ± 1.67 at 80% of gestation, 18.37 ± 1.44 in lambs, and 20.21 ± 2.22 in the adult (ANOVA, F=45.99, P<0.0001). The activity of Na+-K+-ATPase in the cortex increased three-fold from 60% percent of gestation through the postnatal period. An increase was not observed between the newborn and adult groups. Thus, the maximal activity observed was found by day 5 of life. We conclude that ontogenic increases in Na+-K+-ATPase activity are observed from early in fetal to neonatal life, but that after the neonatal period a further increase is not observed.

Expression and function of thrombospondin-1 in myelinating glial cells of the central nervous system.

The thrombospondin (TSP) family of extracellular matrix glycoproteins are widely expressed in the developing and adult central nervous system although their function remains poorly defined. We have used cell culture techniques to analyse the expression and function of TSPs in glial cells derived from myelinated regions of the central nervous system. These experiments show that TSP-1 mRNA, but not TSP-2 or TSP-3 mRNA, is expressed by astrocytes from these regions. TSP-1 mRNA levels in astrocytes are under the regulation of growth factors, being increased by TGFbeta1 and decreased by bFGF. Oligodendrocyte precursors do not express TSP-1, TSP-2, or TSP-3 mRNA. Migration of oligodendrocyte precursor cells is stimulated by TSP-1 substrates as measured either by time-lapse microscopy or using a microchemotaxis chamber assay. Taken together, these results suggest that the extracellular matrix molecule TSP-1 plays a role in normal central nervous system development by contributing to the regulation of oligodendrocyte precursor migration.

Accelerated neuronal differentiation induced by p53 suppression.

p53, a tumor suppressor gene product, has been implicated in the control of cell growth and malignant transformation in different cell types. Here we studied the role of p53 in normal central nervous system development. We show that p53 is expressed in neuroblasts and is down regulated when migrating neurons reach their destination. The suppression of p53 either by the addition of antisense oligonucleotides to culture medium or by the culture of neurons from p53-/- mice accelerated their differentiation. This effect is accompanied by an early induction of MAP1b and a premature dephosphorylation of tau. p53 suppression also reduced levels of p21. Taken collectively these results suggest that the expression of p53 in neuroblasts might prevent neuronal terminal differentiation.

Interplay of T cells and cytokines in the context of enzymatically modified extracellular matrix

The extracellular space consists of approximately a quarter of the volume of the central nervous system (CNS), which is otherwise mostly occupied by cellular elements and blood vessels. This space is filled with various ions, transmitters, metabolites, peptides, and extracellular matrix (ECM) molecules produced by neurons and glia. The best-known ECM domain in brain was recently visualized as “interstitial clefts,” consisting of astrocytic processes enveloped by basal lamina with ECM molecules detected within the clefts. Both the basal lamina and the ECM serve as depots for cytokines and growth factors and both contain proteoglycans, important molecules with the capacity to bind cytokines and growth factors. The ECM components and their ability to store cytokines and growth factors are important in CNS cell development, such as stem cell cytogenesis, synaptic plasticity but also in CNS pathology. It is postulated that most stem cell niches are composed of ECM and other noncellular components that regulate stem cell control and allow for homologous cell–cell interactions as well as stem cell migration toward a damaged tissue. Thus, ECM serves as an immediate source of cytokines and growth factors during normal CNS development, as well as during CNS injury and inflammation. In addition, recent studies have shown that an enzymatic degradation of ECM components may result in uncontrolled diffusion of cytokines and growth factors as well as the activation of the ECM molecules, for example, laminin, therefore contributing to CNS pathology. The information contained in this chapter describes a number of ECM components in the CNS and their role in both normal physiological conditions and CNS injury. The interactions of cytokines and ECM molecules during CNS injury is presented using examples of CNS disease involving either autoimmune (multiple sclerosis), bacterial (meningitis), viral (HIV dementia), or neoplastic (glioma) pathogenic stimuli.

In vivo and in vitro models of medulloblastomas and other primitive neuroectodermal brain tumors of childhood

Recent advances in understanding the basic biology of the neoplastic cells that populate childhood primitive neuroectodermal tumors (PNET) of the central nervous system (CNS) underline several unique properties of these common pediatric brain neoplasms. For example, studies of posterior fossa cerebellar medulloblastomas (MB), a prototypical group of brain tumors that comprise the largest class of PNET, suggest that the molecular phenotype of subpopulations of neoplastic cells in MB partially recapitulates stages in the acquisition of the neuronal phenotype by normal developing human CNS progenitor cells. However, as reviewed here, it appears that the neoplastic cells in MB exhibit one or more molecular defects in the sequence of normal maturational events that enable CNS progenitor cells to exit the cell cycle, become committed to the neuronal lineage, and undergo terminal differentiation into fully mature, permanently postmitotic CNS neurons. Indeed, since PNET emerge almost exclusively in early childhood, the induction of PNET may result from genetic lesions that arise in developing CNS progenitor cells thereby preventing these neural precursors from executing normal programs of lineage commitment and differentiation in the CNS. Clarification of how lineage commitment and maturation in PNET comprised of neuron-like tumor cells deviate from normal CNS development may clarify how oncogenes and tumor suppressor genes exert their effects in a cell type specific manner at different stages in the normal maturation of CNS cells. Recently, a number of potentially effective in vitro and in vivo model systems of PNET have been developed. Since these model systems could facilitate efforts to elucidate mechanisms of neoplastic transformation and tumor progression in the CNS, we review the potential utility of several recently described in vitro (e.g., MB cell lines) and in vivo (e.g., transgenic mice) experimental systems as models of authentic childhood CNS neoplasms.

Developmentally moderated expressions of the neuropathology underlying schizophrenia.

A gradually accumulating body of literature suggests that behavioral dysfunction precedes the onset of the schizophrenic syndrome by many years. Thus, a comprehensive neurodevelopmental model of schizophrenia must encompass these early manifestations of dysfunction as well as the postmorbid period. This article draws on previous research findings as well as recently proposed neurodevelopmental models to offer some further hypotheses about the neurodevelopmental process underlying the changing life-course manifestations of the diathesis for schizophrenia. It is proposed that normal maturational events in the central nervous system moderate the behavioral expression of a congenital neuropathology that affects subcortical regions of the brain that are part of multiple neural circuits. Specifically, it is suggested that the diathesis for schizophrenia involves a functional excess of dopamine activity in the basal ganglia that serves to disrupt these circuits. Findings from empirical research suggest a modal developmental trajectory for schizophrenia in which neuromotor dysfunction is most pronounced in early childhood and late in life, whereas florid psychotic symptomatology is most pronounced in late adolescence and early adulthood. The literature on normal central nervous system development suggests that the feedback circuit linking motor cortex with subcortical structures is maximally metabolically activated, relative to other circuits, early and late in the life course. Thus, subcortical dopamine excess may be predominantly expressed in motoric symptoms during these periods. In contrast, late adolescence and early adulthood are marked by low motor cortex metabolic activity relative to other cortical regions, in particular limbic and frontal regions. In addition, hormonal changes appear to result in a maximal activation of the dopamine system during this developmental period. Thus, it is hypothesized that during this period the neural circuitry abnormality will be primarily behaviorally expressed in psychotic symptoms. Some implications of the model for the study of movement abnormalities and psychotic symptoms are discussed.

Rearrangement of RAG-1 recombinase gene in DNA-repair deficient/immunodeficient "wasted" mice.

Mice recessive for the autosomal gene ``wasted`` wst display a disease pattern which includes increased sensitivity to the killing effects of ionizing radiation, immunodeficiency, and neurologic dysfunction. The recent cloning and characterization of recombinase genes (RAG-l/RAG-2) expressed in lymphoid and possibly central nervous system tissues prompted us to examine expression of these genes in DNA repair-deficient/immunodeficient wasted mice. Our results revealed expression of RAG-1 mRNA in spinal cord (but not brain) of control mice; no expression of RAG-1 mRNA was detected in spinal cord or brain from wst/wst mice or their normal littermates (wst/{center_dot}mice). In thymus tissue, a small RAG-1 transcript (1.0 kb) was detected in wst/wst mice that was not evident in thymus from control mice. In wst/{center_dot}mice, a two-fold increase in RAG-1 mRNA was evident in thymus tissue. RAG-2 mRNA could only be detected in thymus tissue from wst/{center_dot} and not from wst/wst or parental control BCF{sub 1} mice. Southern blots revealed a rearrangement/deletion within the RAG-1 gene of affected wasted mice, not evident in known strain-specific parental or littermate controls. These results support the idea that the RAG-1 gene may map at or near the locus for the wasted mutation. In addition, they suggest the importance of recombinase function in normal immune and central nervous system development as well as the potential contribution of this gene family to the normal repair of radiation-induced DNA damage.

Effects of in Utero Ethanol Exposure on the Developing Serotonergic System

Previous work in this laboratory demonstrated that the 19- and 35-day-old offspring of ethanol-fed rats have a significant deficiency of cortical serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), as well as a decrease in the number of total 5-HT1 receptors in the motor and somatosensory cortex. The present studies extend our previous reports by demonstrating that there is also a deficit of 5-HT and 5-HIAA in the motor cortex but not in the somatosensory cortex. In addition, we have shown that a deficit of 5-HT1A receptors in the motor and somatosensory cortices contributes to the deficit of total 5-HT1 receptors. In contrast, we did not observe any changes in the binding to 5-HT1B receptors in these cortical regions from the 19-day-old offspring of ethanol-fed rats. The present studies also examined the effects of in utero ethanol exposure on the early development of the serotonergic system. The results of these studies demonstrated a deficit of 5-HT and/or 5-HIAA in the brain stem as early as the 15th day of gestation (G15) and in the cortex as early as G19. In addition, we demonstrated a delay in both the normal developmental decline of 5-HT1A receptors in the brain stem and in the acquisition of cortical 5-HT1A receptors. No changes were found in the binding of [125I]cyanopindolol to 5-HT1B receptors in either region of fetal or neonatal rats exposed to ethanol in utero.(ABSTRACT TRUNCATED AT 250 WORDS)

Larsen's syndrome: A skeletal dysplasia with multiple joint dislocations and unusual facies

An infant is described who has multiple joint dislocations, unusual facies, andboney abnormalities, which constitute a syndrome first reported by Larsen. This report expands Larsen's syndrome with the following additional findings: apparent diminished rigidity of cartilage in early infancy, extra finger creases, short fingernails, and an unusual juxtacalcaneal "accessory" bone. Both infant and mother have a flattened nasal bridge. Recognition of this syndrome is important because of the implications for counseling. Affected individuals can be expected to have normal central nervous system development, but the joint abnormalities require prolonged orthopedic treatment; achievement of completely normal function is unlikely.

Development and BEI of full-term and low-birth-weight infants through 18 months.

Serum thyroxine-like iodine compounds (BEI) are essential for normal central nervous system development, but thyroid function tests of full-term and of low-birth-weight infants have not been defined through 18 postnatal months. For 49 full-term infants (normal BEI through five postnatal days 7.2μg to 15.2μg per 100 ml), median and mean BEI from two to six postnatal months were 6.2 ± 0.91 and from 6 to 18 months 5.8μg ± 0.87μg per 100 ml, significantly higher BEI values than for adults. Differences between BEI means of low-birth-weight infants born before and after 34 gestational weeks and of full-term infants were significant at the 0.001 level. Fifteen low-birth-weight infants with BEI determinations until 19 months were examined developmentally; nine, classified normal, appeared to have increasing BEI; six, classified suspect or abnormal, had low or borderline BEI.