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Ethanol Neurotoxicity in the Developing Cerebellum: Underlying Mechanisms and Implications  [PDF]
Ambrish Kumar,Holly A. LaVoie,Donald J. DiPette,Ugra S. Singh
Brain Sciences , 2013, DOI: 10.3390/brainsci3020941
Abstract: Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial few weeks of postnatal development. In this period neuronal maturation and differentiation begin and neuronal cells start migrating to their ultimate destinations. Although the neuronal development of all areas of the brain is affected, the cerebellum and cerebellar neurons are more susceptible to the damaging effects of ethanol. Ethanol’s harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity. Neuronal development requires many hormones and growth factors such as retinoic acid, nerve growth factors, and cytokines. These factors regulate development and differentiation of neurons by acting through various receptors and their signaling pathways. Ethanol exposure during development impairs neuronal signaling mechanisms mediated by the N-methyl-d-aspartate (NMDA) receptors, the retinoic acid receptors, and by growth factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-I), and basic fibroblast growth factor (bFGF). In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain. Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development.
Phenytoin-induced Toxicity in the Postnatal Developing Cerebellum of Wistar Rats, Effect of Calotropis procera on Histomorphometric Parameters
Imosemi,I.O; Osinubi,A.A;
International Journal of Morphology , 2011, DOI: 10.4067/S0717-95022011000200004
Abstract: the role of methanolic leaf extracts of calotropis procera in phenytoin-induced toxicity on histomorphometric variables in the postnatal developing cerebellum of wistar rat was studied. pregnant rats were treated orally with 50 mg/kg phenytoin in pre and post natal life and 300 mg/kg methanolic leaf extract of calotropis procera 1 hour prior to phenytoin administration. 200 mg/kg vitamin c (standard antioxidant) was also administered orally 1 hour prior to phenytoin treatment. the control animals received water. standard diet of rat pellets and water were provided ad libitum. at the end of the experiment, the offspring of days 1, 7, 14, 21, 28 and 50 post partum, five per group were sacrificed by cervical dislocation. the cerebellum of all groups were dissected out and processed for histomorphometric studies. the results showed in the developing cerebellum of phenytoin treated animals, a delayed cell maturation in the external granular layer, reduction of the molecular layer, astrocytic gliosis and loss of purkinje cells on day 50 postpartum. administration of extracts of calotropis procera and vitamin c though reversed these changes when compared with the phenytoin treated group, but not significantly when compared with the control. in conclusion, supplementation with methanolic extracts of calotropis procera reduced the rate at which phenytoin induced toxicity in the postnatal developing cerebellum of wistar rat.
Ischemia Induces Release of Endogenous Amino Acids from the Cerebral Cortex and Cerebellum of Developing and Adult Mice  [PDF]
Simo S. Oja,Pirjo Saransaari
Journal of Amino Acids , 2013, DOI: 10.1155/2013/839036
Abstract: Ischemia enhanced release of endogenous neuroactive amino acids from cerebellar and cerebral cortical slices. More glutamate was released in adult than developing mice. Taurine release enhanced by K+ stimulation and ischemia was more than one magnitude greater than that of GABA or glutamate in the developing cerebral cortex and cerebellum, while in adults the releases were almost comparable. Aspartate release was prominently enhanced by both ischemia and K+ stimulation in the adult cerebral cortex. In the cerebellum K+ stimulation and ischemia evoked almost 10-fold greater GABA release in 3-month olds than in 7-day olds. The release of taurine increased severalfold in the cerebellum of 7-day-old mice in high-K+ media, whereas the K+-evoked effect was rather small in adults. In 3-month-old mice no effects of K+ stimulation or ischemia were seen in the release of aspartate, glycine, glutamine, alanine, serine, or threonine. The releases from the cerebral cortex and cerebellum were markedly different and also differed between developing and adult mice. In developing mice only the release of inhibitory taurine may be large enough to counteract the harmful effects of excitatory amino acids in ischemia in both cerebral cortex and cerebellum, in particular since at that age the release of glutamate and aspartate cannot be described as massive. 1. Introduction Glutamate and γ-aminobutyrate (GABA) are the two major amino acid transmitters in the cerebral cortex and cerebellum, glutamate being responsible for excitatory and GABA for inhibitory transmission [1]. In these higher brain regions glycine was earlier assumed to be only an obligatory cotransmitter in the excitatory N-methyl-D-aspartate- (NMDA-) sensitive glutamate receptors, but more recent studies have also demonstrated the existence and function of strychnine-sensitive inhibitory glycine receptors in these structures [2, 3]. In addition to these established neurotransmitters, taurine also affects neuronal activity as an inhibitory modulator [4]. In the rodent brain the concentrations of taurine are high. In particular, in the developing brain it is the most abundant amino acid, even exceeding the concentration of glutamate [5]. The excessive extracellular accumulation of excitatory amino acids, predominantly that of glutamate but also of aspartate, in ischemia leads to cellular damage in the brain [6, 7]. Their massive release activates glutamate receptors, in particular those of the NMDA class [8], which leads to an excessive influx of Ca2+ and consequent adverse effects [9]. This excitotoxicity may
Alcohol Exposure Decreases CREB Binding Protein Expression and Histone Acetylation in the Developing Cerebellum  [PDF]
Weixiang Guo, Erin L. Crossey, Li Zhang, Stefano Zucca, Olivia L. George, C. Fernando Valenzuela, Xinyu Zhao
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0019351
Abstract: Background Fetal alcohol exposure affects 1 in 100 children making it the leading cause of mental retardation in the US. It has long been known that alcohol affects cerebellum development and function. However, the underlying molecular mechanism is unclear. Methodology/Principal Findings We demonstrate that CREB binding protein (CBP) is widely expressed in granule and Purkinje neurons of the developing cerebellar cortex of na?ve rats. We also show that exposure to ethanol during the 3rd trimester-equivalent of human pregnancy reduces CBP levels. CBP is a histone acetyltransferase, a component of the epigenetic mechanism controlling neuronal gene expression. We further demonstrate that the acetylation of both histone H3 and H4 is reduced in the cerebellum of ethanol- treated rats. Conclusions/Significance These findings indicate that ethanol exposure decreases the expression and function of CBP in the developing cerebellum. This effect of ethanol may be responsible for the motor coordination deficits that characterize fetal alcohol spectrum disorders.
Axonin-1/TAG-1 is required for pathfinding of granule cell axons in the developing cerebellum
Thomas Baeriswyl, Esther T Stoeckli
Neural Development , 2008, DOI: 10.1186/1749-8104-3-7
Abstract: To knock down axonin-1 in a temporally and spatially controlled manner during development of the nervous system, we have combined RNAi with the accessibility of the chicken embryo even at late stages of development. Using ex ovo RNAi, we analyzed the function of axonin-1/TAG-1 in cerebellar development. Axonin-1 is expressed in postmitotic granule cells while they extend their processes, the parallel fibers. In the absence of axonin-1 these processes still extend but no longer in a parallel manner to each other or to the pial surface of the cerebellum.Axonin-1/TAG-1 is required for the navigation, but not for the elongation, of granule cell processes in the developing cerebellum in vivo.Axonin-1 (AX-1)/TAG-1 is a cell adhesion molecule of the immunoglobulin superfamily that was shown to be an axon guidance cue in the central nervous system in vivo [1,2]. Commissural axons in the spinal cord require AX-1 for midline crossing [3]. In the absence of interactions between growth cone AX-1 and floor-plate NrCAM the floor plate is perceived as repulsive and growth cones fail to enter [4]. Sensory neurons from dorsal root ganglia depend on AX-1 for subpopulation-specific navigation to the gray matter of the spinal cord [5]. In the absence of AX-1 function, nociceptive fibers failed to innervate their target layers in the dorsal spinal cord and extended into areas normally innervated by mechanoreceptive fibers. In the cerebellum, AX-1 is expressed in postmitotic granule cells at the time when they extend their processes, the parallel fibers [6-8].The cerebellum is responsible for motor coordination but is also involved in cognitive processes [9,10]. Malformations or damage to the cerebellum have been linked to several human disabilities, including ataxia, cerebral palsy, and epilepsy [9]. In line with the more recent literature describing a contribution of the cerebellum to cognitive processes, changes in cerebellar structure and function have been linked to mental retardati
Dynamic Changes of CD44 Expression from Progenitors to Subpopulations of Astrocytes and Neurons in Developing Cerebellum  [PDF]
Masae Naruse, Koji Shibasaki, Shuichi Yokoyama, Masashi Kurachi, Yasuki Ishizaki
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053109
Abstract: We previously reported that CD44-positive cells were candidates for astrocyte precursor cells in the developing cerebellum, because cells expressing high levels of CD44 selected by fluorescence-activated cell sorting (FACS) gave rise only to astrocytes in vitro. However, whether CD44 is a specific cell marker for cerebellar astrocyte precursor cells in vivo is unknown. In this study, we used immunohistochemistry, in situ hybridization, and FACS to analyze the spatial and temporal expression of CD44 and characterize the CD44-positive cells in the mouse cerebellum during development. CD44 expression was observed not only in astrocyte precursor cells but also in neural stem cells and oligodendrocyte precursor cells (OPCs) at early postnatal stages. CD44 expression in OPCs was shut off during oligodendrocyte differentiation. Interestingly, during development, CD44 expression was limited specifically to Bergmann glia and fibrous astrocytes among three types of astrocytes in cerebellum, and expression in astrocytes was shut off during postnatal development. CD44 expression was also detected in developing Purkinje and granule neurons but was limited to granule neurons in the adult cerebellum. Thus, at early developmental stages of the cerebellum, CD44 was widely expressed in several types of precursor cells, and over the course of development, the expression of CD44 became restricted to granule neurons in the adult.
Implication of Tryptophan 2,3-Dioxygenase and its Novel Variants in the Hippocampus and Cerebellum During the Developing and Adult Brain
Masaaki Kanai, Hiroshi Funakoshi and Toshikazu Nakamura
International Journal of Tryptophan Research , 2012, DOI: 10.4137/IJTR.S4372
Abstract: Tryptophan 2,3-dioxygenase (TDO) is a first and rate-limiting enzyme for the kynurenine pathway of tryptophan metabolism. Using Tdo-/-mice, we have recently shown that TDO plays a pivotal role in systemic tryptophan metabolism and brain serotonin synthesis as well as emotional status and adult neurogenesis. However, the expression of TDO in the brain has not yet been well characterized, in contrast to its predominant expression in the liver. To further examine the possible role of local TDO in the brain, we quantified the levels of tdo mRNA in various nervous tissues, using Northern blot and quantitative real-time RT-PCR. Higher levels of tdo mRNA expression were detected in the cerebellum and hippocampus. We also identified two novel variants of the tdo gene, termed tdo variant1 and variant2, in the brain. Similar to the known TDO form (TDO full-form), tetramer formation and enzymatic activity were obtained when these variant forms were expressed in vitro. While quantitative real-time RT-PCR revealed that the tissue distribution of these variants was similar to that of tdo full-form, the expression patterns of these variants during early postnatal development in the hippocampus and cerebellum differed. Our findings indicate that in addition to hepatic TDO, TDO and its variants in the brain might function in the developing and adult nervous system. Given the previously reported associations of tdo gene polymorphisms in the patients with autism and Tourette syndrome, the expression of TDO in the brain suggests the possible influence of TDO on psychiatric status. Potential functions of TDOs in the cerebellum, hippocampus and cerebral cortex under physiological and pathological conditions are discussed.
Implication of Tryptophan 2,3-Dioxygenase and its Novel Variants in the Hippocampus and Cerebellum During the Developing and Adult Brain
Masaaki Kanai,Hiroshi Funakoshi,Toshikazu Nakamura
International Journal of Tryptophan Research , 2010,
Abstract: Tryptophan 2,3-dioxygenase (TDO) is a first and rate-limiting enzyme for the kynurenine pathway of tryptophan metabolism. Using Tdo-/-mice, we have recently shown that TDO plays a pivotal role in systemic tryptophan metabolism and brain serotonin synthesis as well as emotional status and adult neurogenesis. However, the expression of TDO in the brain has not yet been well characterized, in contrast to its predominant expression in the liver. To further examine the possible role of local TDO in the brain, we quantified the levels of tdo mRNA in various nervous tissues, using Northern blot and quantitative real-time RT-PCR. Higher levels of tdo mRNA expression were detected in the cerebellum and hippocampus. We also identified two novel variants of the tdo gene, termed tdo variant1 and variant2, in the brain. Similar to the known TDO form (TDO full-form), tetramer formation and enzymatic activity were obtained when these variant forms were expressed in vitro. While quantitative real-time RT-PCR revealed that the tissue distribution of these variants was similar to that of tdo full-form, the expression patterns of these variants during early postnatal development in the hippocampus and cerebellum differed. Our findings indicate that in addition to hepatic TDO, TDO and its variants in the brain might function in the developing and adult nervous system. Given the previously reported associations of tdo gene polymorphisms in the patients with autism and Tourette syndrome, the expression of TDO in the brain suggests the possible influence of TDO on psychiatric status. Potential functions of TDOs in the cerebellum, hippocampus and cerebral cortex under physiological and pathological conditions are discussed.
FGF/FGFR2 Signaling Regulates the Generation and Correct Positioning of Bergmann Glia Cells in the Developing Mouse Cerebellum  [PDF]
Florian Meier, Florian Giesert, Sabit Delic, Theresa Faus-Kessler, Friederike Matheus, Antonio Simeone, Sabine M. H?lter, Ralf Kühn, Daniela M. Vogt. Weisenhorn, Wolfgang Wurst, Nilima Prakash
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101124
Abstract: The normal cellular organization and layering of the vertebrate cerebellum is established during embryonic and early postnatal development by the interplay of a complex array of genetic and signaling pathways. Disruption of these processes and of the proper layering of the cerebellum usually leads to ataxic behaviors. Here, we analyzed the relative contribution of Fibroblast growth factor receptor 2 (FGFR2)-mediated signaling to cerebellar development in conditional Fgfr2 single mutant mice. We show that during embryonic mouse development, Fgfr2 expression is higher in the anterior cerebellar primordium and excluded from the proliferative ventricular neuroepithelium. Consistent with this finding, conditional Fgfr2 single mutant mice display the most prominent defects in the anterior lobules of the adult cerebellum. In this context, FGFR2-mediated signaling is required for the proper generation of Bergmann glia cells and the correct positioning of these cells within the Purkinje cell layer, and for cell survival in the developing cerebellar primordium. Using cerebellar microexplant cultures treated with an FGFR agonist (FGF9) or antagonist (SU5402), we also show that FGF9/FGFR-mediated signaling inhibits the outward migration of radial glia and Bergmann glia precursors and cells, and might thus act as a positioning cue for these cells. Altogether, our findings reveal the specific functions of the FGFR2-mediated signaling pathway in the generation and positioning of Bergmann glia cells during cerebellar development in the mouse.
Neuroprotective Effect of Dexamethasone on the Morphology of the Irradiated Post Natal Developing Cerebellum of Wistar Rat (Rattus norvegicus)
Malomo,A. O.; Ekpo,O. E.; Imosemi,I. O.; Owoeye,O.; Osuagwu,F. C.; Avwioro,O. G.; Shokunbi,M.T.;
International Journal of Morphology , 2006, DOI: 10.4067/S0717-95022006000300017
Abstract: the neuroprotective effect of dexamethasone on the irradiated postnatal developing cerebellum of wistar rat was studied. seventy-five (day 1 old) neonates were separated into three groups; control group receiving no drug and no irradiation, irradiated group, and irradiated and dexamethasone group in which the dexamethasone was administered one hour before exposure to 5gray (5gy) of gamma rays. on complete exposure to the various interventions, the cerebellar tissues of animals from each group on days 5, 9, 14, 21 and 25 were processed for histological and histomorphometric studies. the result of the study showed that irradiation alone significantly reduced the thickness of the external granular layer (egl) on day 5 and 14 at p<0.05, molecular layer (ml) on days 5, 9, 14 and 21 at p<0.05 and the granule layer (gl) on days 5, 9, 14 and 25 at p<0.05. when dexamethasone was combined with irradiation, a thicker and significantly different egl on days 5, 9 and 14, ml on days 5, 14 and 21, and gl on days 5 and 14 was observed compared with the irradiated group at p<0.05. the purkinje cell (pc) diameter even though was significantly reduced in the irradiated group on days 14 and 21, was not significantly different when dexamethasone was administered to the irradiated animals on days 5, 9, 14, 21 and 25 at p>0.05. histologically, the cells of the ml in the irradiated group on days 9 and 14 were heavily gliosed compared to the mildly gliosed control, and the irradiated and dexamethasone groups. there was distortion of the pc monolayer with some cells found in either the ml or gl in the irradiated group on days 5, 9, 14 and 25. from the result of the study, administration of 0.005ml dexamethasone intraperitoneallyone hour before exposure to irradiation appeared to protect the developing rat cerebellum against irradiation injury as seen when compared with the controls
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