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Results for “Astrocyte morphology”

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PubMed1998

Homotypic cell contact-dependent inhibition of astrocyte proliferation.

The normal adult vertebrate nervous system is a relative quiescent tissue in terms of cell proliferation. However, astrocytes in many regions of the central nervous system (CNS) retain the capacity to undergo cell division. To examine the mechanisms that regulate the proliferation of astrocytes in the CNS we have utilized an in vitro assay in which astrocyte density and cellular environment could be regulated. We demonstrate that type 1 astrocytes derived from the cerebral cortex of developing rats exhibit a profound density-dependent inhibition of proliferation. This inhibition of proliferation was cell type specific, but not restricted to type 1 astrocytes. NIH 3T3 cells but not smooth muscle cells inhibited astrocyte proliferation, while contact-inhibited astrocytes did not inhibit oligodendrocyte proliferation. Co-culture of type 1 astrocytes with neurons from a variety of sources resulted in induction of a process-bearing astrocyte morphology and promoted glial cell proliferation. Thus, induction of a process-bearing astrocyte morphology does not lead to a cessation of proliferation. The inhibition of astrocyte proliferation did not appear to be mediated through the release or sequestration of soluble factors but rather could be induced by membrane-associated factors.

Animals↗
PubMed2000

The GLT-1 and GLAST glutamate transporters are expressed on morphologically distinct astrocytes and regulated by neuronal activity in primary hippocampal cocultures.

The GLT-1 and GLAST astroglial transporters are the glutamate transporters mainly involved in maintaining physiological extracellular glutamate concentrations. Defects in neurotransmitter glutamate transport may represent an important component of glutamate-induced neurodegenerative disorders (such as amyotrophic lateral sclerosis) and CNS insults (ischemia and epilepsy). We characterized the protein expression of GLT-1 and GLAST in primary astrocyte-neuron cocultures derived from rat hippocampal tissues during neuron differentiation/maturation. GLT-1 and GLAST are expressed by morphologically distinct glial fibrillary acidic protein-positive astrocytes, and their expression correlates with the status of neuron differentiation/maturation and activity. Up-regulation of the transporters paralleled the content of the synaptophysin synaptic vesicle marker p38, and down-regulation was a consequence of glutamate-induced neuronal death or the reduction of synaptic activity. Finally, soluble factors in neuronal-conditioned media prevented the down-regulation of the GLT-1 and GLAST proteins. Although other mechanisms may participate in regulating GLT-1 and GLAST in the CNS, our data indicate that soluble factors dependent on neuronal activity play a major regulating role in hippocampal cocultures.

ATP-Binding Cassette Transporters↗
PubMed1996

Characterization of the morphological variations of astrocytes in culture following ethanol exposure.

The nervous system is one of the main targets of ethanol toxicity and it has been suggested that astrocytes might play an important role as their integrity is essential for the normal growth and functioning of neurons. Morphological variations of astrocyte cultures were therefore examined after exposure to various doses of ethanol (0.5, 1 and 2%) for different durations (24, 48, 72 and 96 h). The percentage of cell viability and the cell density were calculated and the changes in astrocyte morphology were assessed by an image analysis system (Samba 2005) allowing the characterization of 5 parameters (perimeter, surface, elongation factor, convexity factor and the form factor) of a great number of cells (over 6500). This was necessary because of the high variability in normal cultured astrocyte morphology. A two-way statistical approach (2-factors ANOVA completed by stepwise discriminant analysis) was adopted to emphasize the differences between control and exposed cells. In such conditions, ethanol treated cells became more elongated, less circular and more concave and did not grow like non-exposed cells. The mean pooled values of these parameters tended to be modified as a function of the dose of ethanol. The relationships between parameters clearly separated the groups as a function of the different doses. Finally no significant difference was observed in cell viability and cell density despite lower scores in the groups exposed to the highest dose of ethanol for the longest time. Our results suggest that ethanol might affect astrocytes in two different but probably complementary ways by modifying the cell shape and by altering normal cell development.

Animals↗
PubMed1985

Localization of immunoglobulins G, A and M in glial cells of reactive and neoplastic origin.

The localization of immunoglobulins G, A and M in glial cells of neoplastic and reactive origin have been investigated by the use of the PAP (peroxidase-antiperoxidase) method on paraffin embedded tissue previously fixed in calcium formol. It has been found, that some glial cells of astrocyte type showed a very intense staining when oligoclonal antibodies to human immunoglobulins G, A and M specific for gamma, alpha, and mu chains were used. The localization of immunoglobulins was disclosed in astrocytes of various morphology; astrocytes with well developed processes, gemistocyte type cells without or only with short and thick cell processes and in small cells with scanty cytoplasm. The number of cells with immunoglobulins localized is very small. No positive results have been noted if the normal brain tissue is concerned. The specificity of the method is discussed.

Astrocytes↗
PubMed2001

Na+ and K+ dependence of L-glutamate-induced suppression of astrocyte stellation in culture.

We have recently found that L-glutamate suppresses astrocyte stellation induced by various stimuli, and that this effect of L-glutamate is mimicked by transportable glutamate uptake inhibitors. To test the possible role of the glutamate transporter in the regulation of astrocyte morphology, we investigated the Na+ and K+ dependence of this effect of L-glutamate. In astrocyte cultures obtained from the cerebral cortex of neonatal rats, the L-glutamate-induced suppression of astrocyte stellation was significantly attenuated in a low- Na+/high- K+ medium and by the Na+ -K+ pump inhibitor ouabain. These results support that astrocyte morphology is affected by the activity of the Na+ -dependent glutamate transporter.

Animals↗
PubMed1999

Astrocyte stellation induced by tyrosine kinase inhibitors in culture.

To understand the role of tyrosine kinases in regulation of astrocyte morphology, we investigated the effects of tyrosine kinase inhibitors on morphology of cultured rat cortical astrocytes. Cultured astrocytes exhibited flattened, polygonal morphology in the absence of stimulation, but changed into process-bearing stellate cells in the presence of the tyrosine kinase inhibitor genistein (3-100 microM). Genistein-induced astrocyte stellation was abolished by treatment with colchicine or paclitaxel, indicating the involvement of cytoskeletal elements. The effect of genistein was mimicked by another tyrosine kinase inhibitor herbimycin A, but not by daidzein, an inactive analog of genistein. These results suggest that tyrosine kinases are in an activated state in the absence of stimuli and contribute to the maintenance of polygonal morphology of cultured astrocytes.

Animals↗
PubMed2003

Astrocyte stellation induced by Rho kinase inhibitors in culture.

To understand the role of Rho kinases in regulation of astrocyte morphology, we investigated the effects of Rho kinase inhibitors on the morphology of cultured rat cortical astrocytes. Cultured astrocytes exhibited flattened, polygonal morphology in the absence of stimulation, but changed into process-bearing stellate cells following treatment with the selective Rho kinase inhibitor Y-27632 (1-10 microM). The Y-27632-induced astrocyte stellation was abolished by treatment with colchicine, indicating that the response requires reorganization of cytoskeletal elements. The effect of Y-27632 was mimicked by another Rho kinase inhibitor HA1077, but not by the protein kinase C inhibitor GF-109203X or the protein kinase A inhibitor KT5720. These results suggest that Rho kinases are in an activated state in the absence of stimuli and contribute to the maintenance of polygonal morphology of cultured astrocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Neurobiology of ammonia.

Hyperammonemia resulting from inherited urea cycle enzyme deficiencies or liver failure results in severe central nervous system dysfunction including brain edema, convulsions and coma. Neuropathologic evaluation in these disorders reveals characteristic alterations of astrocyte morphology ranging from cell swelling (acute hyperammonemia) to Alzheimer Type II astrocytosis (chronic hyperammonemia). Having no effective urea cycle, brain relies on glutamine synthesis for the removal of excess ammonia and the enzyme responsible, glutamine synthetase, has a predominantly astrocytic localization. Accumulation of ammonia in brain results in a redistribution of cerebral blood flow and metabolism from cortical to sub-cortical structures. In addition to changes in astrocyte morphology, increased brain ammonia concentrations result in alterations in expression of key astrocyte proteins including glial fibrillary acidic protein, glutamate and glycine transporters and "peripheral-type" (mitochondrial) benzodiazepine receptors. Such changes result in alterations of astrocytic volume and increased extracellular concentrations of excitatory and inhibitory substances. In addition, the ammonium ion has direct effects on excitatory-inhibitory transmission via distinct mechanisms involving cellular chloride extrusion and postsynaptic receptor function. Acute ammonia exposure leads to activation of NMDA receptors and their signal transduction pathways. Chronic hyperammonemia also results in increased concentrations of neuroactive L-tryptophan metabolites including serotonin and quinolinic acid. Therapy in hyperammonemic syndromes continues to rely on ammonia-lowering strategies via peripheral mechanisms (reduction of ammonia production in the gastrointestinal tract, increased ammonia removal by muscle).

Ammonia↗
PubMed1996

Redistribution and degeneration of retinal astrocytes in experimental murine cerebral malaria: relationship to disruption of the blood-retinal barrier.

To determine whether astrocytes play a critical role in the pathogenesis of experimental murine cerebral malaria (EMCM), we examined changes in astrocyte morphology and distribution, using retinal wholemounts, in three models: a fatal cerebral malaria (CM) model, in which mice die showing cerebral symptoms; a "resolving" model, in which mice exhibit mild cerebral symptoms, but then recover; and a non-CM model, in which cerebral symptoms are not seen. In the fatal model, retinal astrocytes lost their even distribution from day 3 post-inoculation (p.i.) with malaria parasites, progressing to gliosis (day 5 p.i.), well before the onset of cerebral symptoms on day 6-7 p.i. At the terminal stage of the disease there was a loss of astrocyte processes contacting retinal vessels, often along vessel segments containing adherent monocytes. These features occurred in a mild form in the resolving model and were absent in the non-CM models. To investigate the mechanisms underlying these astrocytic changes, we carried out two experimental manipulations. Firstly, since dexamethasone ameliorates cerebral complications in the fatal CM model, the astrocytic response was monitored after dexamethasone treatment on days 0 and 1 p.i., or days 3 and 4 p.i. Second, to determine whether increased blood-retinal barrier (BRB) permeability initiates the astrocyte changes, breakdown of the BRB was induced experimentally by intra-carotid injection of arabinose and astrocyte morphology and distribution were examined 12, 24, and 48 h later. Retinal astrocytes in both the dexamethasone- and the arabinose-treated groups showed loss of even astrocyte distribution but no loss of astrocyte ensheathment of vessels. It is concluded that: i) astrocytes are involved in the pathogenesis of EMCM, since these changes are only prominent in the fatal model and occur substantially before the onset of cerebral symptoms; ii) the initial changes in astrocyte distribution may be a consequence of the increase in BRB permeability; and iii) the immune response triggered by the malaria parasite may be responsible for the loss of astrocyte ensheathment of vessel segments.

Animals↗
PubMed1999

Effects of Cerebrolysin on in vitro primary microglial and astrocyte rat cell cultures.

In recent years the potential use of neurotrophic factors in the prevention and/or treatment of neurodegenerative diseases has received much attention. To determine whether Cerebrolysin, a porcine brain-derived peptide preparation, was able to modulate in vitro lipopolysaccharide (LPS)-induced microglial activation and to test the direct effect of Cerebrolysin on astrocyte morphology, survival and proliferation, rat glial and astrocyte cell culture experiments were carried out. The morphology of microglia, ameboid/activated and flat/resting, was examined under contrast microscopy and cell counts obtained. In addition, the release of interleukin (IL)-1 beta and brain-derived neurotrophic factor (BDNF) was measured from cell culture supernatant using an enzyme-linked-immunoassay (ELISA). The results obtained in this study clearly suggest a protective effect of Cerebrolysin as revealed by downregulation of microglial activation after LPS treatment as well as by the control of IL-1 beta expression. No significant differences were observed on astrocyte morphology, survival or the production and/or release of BDNF. In conclusion, these in vitro studies indicate that Cerebrolysin might exert a neuroimmunotrophic function which can in turn reduce the extent of inflammation and accelerate neuronal death under pathological conditions such as human neurodegenerative disorders.

Amino Acids↗
PubMed2002

GABA mediates steroid-induced astrocyte differentiation in the neonatal rat hypothalamus.

Our previous work has demonstrated that astrocytes in the developing arcuate nucleus of the rat hypothalamus are sexually dimorphic as a result of differential exposure to oestradiol. Moreover, our experiments in neonatal rats suggest an absence of oestrogen receptors (ER) in arcuate nucleus astrocytes in vivo. This, along with the conspicuous lack of evidence in the literature confirming the presence of ER in arcuate nucleus astrocytes of the neonatal rat brain, led us to question the mechanism by which oestrogen induces changes in arcuate nucleus astrocyte morphology. Based on our previous findings that oestradiol increases gamma-aminobutyric acid (GABA) levels in the neonatal rat arcuate, we hypothesize that GABA is released from neighbouring oestrogen-sensitive neurones and alters arcuate nucleus astrocyte morphology. Here, we report that in vivo reduction of GABA synthesis in the neonatal rat brain by antisense oligodeoxynucleotides to glutamic acid decarboxylase prevented gonadal steroid-induced astrocyte differentiation in males and testosterone-treated females. Conversely, activation of GABAA receptors with the agonist muscimol increased astrocyte differentiation in females in the absence of gonadal steroids. Given that GABA is made only in neurones and that its synthesis is increased by oestradiol, we conclude that it acts as a diffusible factor inducing the differentiation of neighbouring astrocytes.

Animals↗
PubMed1988

Phorbol ester and dibutyryl cyclic AMP reduce content and efflux of taurine in primary cerebellar astrocytes in culture.

In 16-18 days in vitro (DIV) primary astrocyte cultures prepared from 7- to 9-day-old rats, 48 h exposure to 12,13-phorbol dibutyrate (PDBU) (1 microM) or dibutyryl cAMP (dbcAMP) (1 mM) reduced cellular taurine content, and both basal and 50 mM K+-evoked taurine efflux, but did not alter cellular glutamate or total protein content. Decreases in cellular taurine content first became apparent between 1 and 6 h and were maximal after 24 h. Treatment also rapidly altered astrocyte morphology to a more process-bearing form within 1 h. In contrast, fibroblast growth factor (FGF), epidermal growth factor (EGF), dbcGMP and alpha-PDBU did not affect cellular morphology, amino acid content or taurine efflux at any time tested. These findings suggest that, while protein kinase C translocation and adenylate cyclase activation may be only indirectly involved in the regulation of astrocyte morphology, long-term decreases in cellular taurine content and efflux may be the more direct result of these second messenger systems.

Animals↗
PubMed2007

Differential expression patterns of chloride transporters, Na+-K+-2Cl--cotransporter and K+-Cl--cotransporter, in epilepsy-associated malformations of cortical development.

Malformations of cortical development are recognized causes of chronic medically intractable epilepsy. An increasing number of observations suggests an important role for cation-chloride co-transporters (CCTs) in controlling neuronal function. Deregulation of their expression may contribute to the mechanisms of hyperexcitability that lead to seizures. In the present study the expression and cell-specific distribution of Na+-K+-2Cl--cotransporter (NKCC1) and K+-Cl--cotransporter (KCC2) were studied immunocytochemically in different developmental lesions, including focal cortical dysplasia (FCD) type IIB (n=9), hemimegalencephaly (HMEG, n=6) and ganglioglioma (GG, n=9) from patients with medically intractable epilepsy and in age-matched controls. In normal control adult cortex, NKCC1 displayed low neuronal and glial expression levels. In contrast KCC2 showed strong and diffuse neuropil staining. Notable glial immunoreactivity (IR) was not found for KCC2. NKCC1 was highly expressed in the majority of FCD, HMEG and GG specimens. NKCC1 IR was observed in neurons of different size, including large dysplastic neurons, in balloon cells (in FCD and HMEG cases) and in glial cells with astrocytic morphology. The immunoreactivity pattern of KCC2 in FCD, HMEG and GG specimens was characterized by less neuropil staining and more intrasomatic IR compared with control. KCC2 IR was observed in neurons of different size, including large dysplastic neurons, but not in balloon cells or in glial cells with astrocytic morphology. Double-labeling experiments confirmed the differential cellular distribution of the two CCTs and their expression in GABA(A) receptor (alpha1 subunit)-positive dysplastic neurons. The cellular distribution of CCTs, with high expression of NKCC1 in dysplastic neurons and altered subcellular distribution of KCC2 resembles that of immature cortex and suggests a possible contribution of CCTs to the high epileptogenicity of malformations of cortical development.

Adolescent↗
PubMed2007

Evidence for a wide extra-astrocytic distribution of S100B in human brain.

BACKGROUND: S100B is considered an astrocytic in-situ marker and protein levels in cerebrospinal fluid (CSF) or serum are often used as biomarker for astrocytic damage or dysfunction. However, studies on S100B in the human brain are rare. Thus, the distribution of S100B was studied by immunohistochemistry in adult human brains to evaluate its cell-type specificity. RESULTS: Contrary to glial fibrillary acidic protein (GFAP), which selectively labels astrocytes and shows only faint ependymal immunopositivity, a less uniform staining pattern was seen in the case of S100B. Cells with astrocytic morphology were primarily stained by S100B in the human cortex, while only 20% (14-30%) or 14% (7-35%) of all immunopositive cells showed oligodendrocytic morphology in the dorsolateral prefrontal and temporal cortices, respectively. In the white matter, however, most immunostained cells resembled oligodendrocytes [frontal: 75% (57-85%); temporal: 73% (59-87%); parietal: 79% (62-89%); corpus callosum: 93% (86-97%)]. S100B was also found in ependymal cells, the choroid plexus epithelium, vascular endothelial cells, lymphocytes, and several neurones. Anti-myelin basic protein (MBP) immunolabelling showed an association of S100B with myelinated fibres, whereas GFAP double staining revealed a distinct subpopulation of cells with astrocytic morphology, which solely expressed S100B but not GFAP. Some of these cells showed co-localization of S100B and A2B5 and may be characterized as O2A glial progenitor cells. However, S100B was not detected in microglial cells, as revealed by double-immunolabelling with HLA-DR. CONCLUSION: S100B is localized in many neural cell-types and is less astrocyte-specific than GFAP. These are important results in order to avoid misinterpretation in the identification of normal and pathological cell types in situ and in clinical studies since S100B is continuously used as an astrocytic marker in animal models and various human diseases.

Adult↗
PubMed2005

Regulation of glutamate transporters in astrocytes: evidence for a relationship between transporter expression and astrocytic phenotype.

The astrocytic glutamate transporters, EAAT1 and EAAT2, remove released L-glutamate from the synaptic milieu thereby maintaining normal excitatory transmission. EAAT dysfunction during the excitotoxicity and oxidative stress of neurological insults may involve homoeostatic mechanisms associated with astrocytic function. We investigated aspects of EAAT function and expression in concert with astrocytic phenotype in primary cultures of cortical astrocytes and mixed cells of the spinal cord. In spinal cord mixed cultures, hydrogen peroxide (300 microM) reduced both EAAT activity and cellular viability to half of their basal values at 24 h post-treatment, but at 2 h EAAT activity was unaltered, while cellular viability was significantly decreased, suggestive of a mechanism for the maintenance of EAAT activity. Cytochemistry for MAP2, GFAP and propidium iodide revealed that neurons and astrocytes were damaged in a time-dependent manner. A change in astrocyte morphology was observed, with astrocyte cell bodies becoming larger and processes becoming more stellate and often shorter in length. EAAT1 immunoreactivity was reduced at 24 h post-treatment and a re-distribution of the protein was noted after 2 h treatment. In pure astrocytes, lipopolysaccharide (1 microg/ml, 3 d) increased [3H]D-aspartate uptake by 90%, as well EAAT1 immunoreactivity and astrocyte stellation, as shown by immunofluorescent labelling for GFAP. In both culture systems, prominent changes were noted in EAAT function and localization in conjunction with altered astrocytic phenotype. Our findings are indicative of a relationship between astrocytic phenotype and the level of EAAT activity that may be a vital component of astrocytic homeostatic responses in brain injury.

Animals↗
PubMed2006

Hes6 inhibits astrocyte differentiation and promotes neurogenesis through different mechanisms.

The mechanisms regulating the generation of cell diversity in the mammalian cerebral cortex are beginning to be elucidated. In that regard, Hairy/Enhancer of split (Hes) 1 and 5 are basic helix-loop-helix (bHLH) factors that inhibit the differentiation of pluripotent cortical progenitors into neurons. In contrast, a related Hes family member termed Hes6 promotes neurogenesis. It is shown here that knockdown of endogenous Hes6 causes supernumerary cortical progenitors to differentiate into cells that exhibit an astrocytic morphology and express the astrocyte marker protein GFAP. Conversely, exogenous Hes6 expression in cortical progenitors inhibits astrocyte differentiation. The negative effect of Hes6 on astrocyte differentiation is independent of its ability to promote neuronal differentiation. We also show that neither its proneuronal nor its anti-gliogenic functions appear to depend on Hes6 ability to bind to DNA via the basic arm of its bHLH domain. Both of these activities require Hes6 to be localized to nuclei, but only its anti-gliogenic function depends on two short peptides, LNHLL and WRPW, that are conserved in all Hes6 proteins. These findings suggest that Hes6 is an important regulator of the neurogenic phase of cortical development by promoting the neuronal fate while suppressing astrocyte differentiation. They suggest further that separate molecular mechanisms underlie the proneuronal and anti-gliogenic activities of Hes6 in cortical progenitor cells.

Animals↗