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PubMed1997

Control of the phosphorylation of the astrocyte marker glial fibrillary acidic protein (GFAP) in the immature rat hippocampus by glutamate and calcium ions: possible key factor in astrocytic plasticity.

The present review describes recent research on the regulation by glutamate and Ca2+ of the phosphorylation state of the intermediate filament protein of the astrocytic cytoskeleton, glial fibrillary acidic protein (GFAP), in immature hippocampal slices. The results of this research are discussed against a background of modern knowledge of the functional importance of astrocytes in the brain and of the structure and dynamic properties of intermediate filament proteins. Astrocytes are now recognized as partners with neurons in many aspects of brain function with important roles in neural plasticity. Site-specific phosphorylation of intermediate filament proteins, including GFAP, has been shown to regulate the dynamic equilibrium between the polymerized and depolymerized state of the filaments and to play a fundamental role in mitosis. Glutamate was found to increase the phosphorylation state of GFAP in hippocampal slices from rats in the post-natal age range of 12-16 days in a reaction that was dependent on external Ca2+. The lack of external Ca2+ in the absence of glutamate also increased GFAP phosphorylation to the same extent. These effects of glutamate and Ca2+ were absent in adult hippocampal slices, where the phosphorylation of GFAP was completely Ca(2+)-dependent. Studies using specific agonists of glutamate receptors showed that the glutamate response was mediated by a G protein-linked group II metabotropic glutamate receptor (mGluR). Since group II mGluRs do not act by liberating Ca2+ from internal stores, it is proposed that activation of the receptor by glutamate inhibits Ca2+ entry into the astrocytes and consequently down-regulates a Ca(2+)-dependent dephosphorylation cascade regulating the phosphorylation state of GFAP. The functional significance of these results may be related to the narrow developmental window when the glutamate response is present. In the rat brain this window corresponds to the period of massive synaptogenesis during which astrocytes are known to proliferate. Possibly, glutamate liberated from developing synapses during this period may signal an increase in the phosphorylation state of GFAP and a consequent increase in the number of mitotic astrocytes.

Animals↗

PubMed1999

Human immunodeficiency virus-1-infected macrophages induce inducible nitric oxide synthase and nitric oxide (NO) production in astrocytes: astrocytic NO as a possible mediator of neural damage in acquired immunodeficiency syndrome.

Nitric oxide (NO) plays an important role in normal neural cell function. Dysregulated or overexpression of NO contributes to neurologic damage associated with various pathologies, including human immunodeficiency virus (HIV)-associated neurological disease. Previous studies suggest that HIV-infected monocyte-derived macrophages (MDM) produce low levels of NO in vitro and that inducible nitric oxide synthase (iNOS) is expressed in the brain of patients with neurologic disease. However, the levels of NO could not account for the degree of neural toxicity observed. In this study, we found that induction of iNOS with concomitant production of NO occurred in primary human astrocytes, but not in MDM, when astrocytes were cocultured with HIV-1-infected MDM. This coincided with decreased HIV replication in infected MDM. Supernatants from cocultures of infected MDM and astrocytes also stimulated iNOS/NO expression in astrocytes, but cytokines known to induce iNOS expression (interferon-gamma, interleukin-1beta, and tumor necrosis factor-alpha) were not detected. In addition, the recombinant HIV-1 envelope protein gp41, but not rgp120, induced iNOS in cocultures of uninfected MDM and astrocytes. This suggests that astrocytes may be an important source of NO production due to dysregulated iNOS expression and may constitute one arm of the host response resulting in suppression of HIV-1 replication in the brain. It also leads us to speculate that neurologic damage observed in HIV disease may ensue from prolonged, high level production of NO.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Hyaluronate receptor CD44 is expressed by astrocytes in the adult chicken and in astrocyte cell precursors in early development of the chick spinal cord.

The role of the hyaluronate receptor, CD44, is well known in adult mammal astrocytes where it modulates neuron-glia interactions. However, no data exist regarding its expression in other vertebrates during their development. In order to detect the expression of CD44 in the chicken and its possible involvement in glial precursor migratory patterns during spinal cord development, a monoclonal antibody (MoAb) against the mammalian standard isoform, CD44-H, was used in immunohistochemical and immunoblot assays. With these methods, CD44 hyaluronate receptors were found on mature astrocyte membranes of adult chicken spinal cord. Astrocytes were identified using a MoAb against GFAP. During development, small clusters of CD44 labelled cells were seen lining the central canal starting from embryonic stage E10. These labelled cells were dispersed in the dorsal, lateral and ventral funiculi of the spinal cord in the subsequent stages. After stage E15, the CD44 labelled cells were identified as astrocytes because of their GFAP immunoreactivity. We conclude that CD44 receptors on immature astrocyte precursors should be considered as early astrocyte markers which have a possible role during cell migratory dispersal.

Animals↗

PubMed1980

Specialized contacts of astrocytes with astrocytes and with other cell types in the hypothalamus of the hamster.

Adult hamsters were used for this electron microscopic study of the hypothalamic region. Specialized contacts between astrocytes and astrocytes, and between astrocytes and other cellular elements, are described and illustrated. The specialized inter-astrocytic junctions occur primarily in perivascular and subpial regions, but also in areas of high synaptic density. The junctions between astrocytic processes are of hemidesmosomal type. Astrocytes are connected to oligodendroglial cells by means of desmosomes, and to neuronal processes by means of zonulae occludens. The functional significance of these arrangements is discussed.

Animals↗

PubMed1997

A common morphological response of astrocytes to various injuries: "dark" astrocytes. A light and electron microscopic analysis.

Our previous studies showed that neurons became argyrophilic following different kinds of brain injuries. In the present study we demonstrated that astrocytes could also become argyrophilic following compressive or concussive head injuries and following intraperitoneal administration of pentylenetetrazole or kainic acid. Furthermore the soma, nucleus and processes of these argyrophilic astrocytes were shown in other preparations to be hyper-basophilic with the light microscope, and hyper-electron dense and shrunken at the ultrastructural level. When the head injuries were inflicted either at the 15th min. of perfusion-fixation or at the 30th min. of transcardial perfusion with chilled physiological saline, several astrocytes also became argyrophilic, hyper-basophilic, shrunken and hyper-electron dense. These data indicate that (i) the intracellular pathological event in these astrocytes is similar to that of "dark" neurons or "dark" cells of non-neural tissues, (ii) the formation of "dark" astrocytes can be independent of the actual state of metabolism, and (iii) the "dark" morphological state of astrocytes might have a role in neuropathological processes.

Animals↗

PubMed1996

The 5HT5A serotonin receptor is expressed predominantly by astrocytes in which it inhibits cAMP accumulation: a mechanism for neuronal suppression of reactive astrocytes.

The mRNA for the 5-hydroxytryptamine receptor 5-HT5A was detected at embryonic day 18 in the rat central nervous system and peaked by postnatal day 20. At all time points examined, 5-HT5A immunoreactivity observed on astrocyte cell bodies and in the stellate processes not only colocalized with the astrocyte-specific marker glial fibrillary acidic protein (GFAP) but was coordinately regulated with GFAP, increasing during development and during gliosis. Transfection of 5-HT5A into glioma cells prevented the 5-HT-induced increase in cAMP observed in untransfected cells and decreased the relative forskolin response by approximately 20%, suggesting that the 5-HT5A receptor couples negatively to adenylyl cyclase in astrocytes. Together, these results indicate a neuron-to-astrocyte serotonergic signaling pathway mediating cAMP concentrations, which could provide a neuronally driven mechanism for regulating astrocyte physiology with relevance to gliosis.

Aging↗

PubMed1975

Specialized contacts of astrocytes with astrocytes and with other cell types in the spinal cord of the cat.

Adult and half grown healthy male and female cats were used in this study. The white and gray matter of dorsolateral region in the upper lumbar levels of the spinal cord were examined by electron microscopy after fixation by aldehyde perfusion and commonly used methods of embedding, sectioning and staining. The report is limited to description and illustration of specialized junctions of astrocytes. In addition to previously described astrocyte-astrocyte gap junctions, astrocytes are connected by gap junctions to oligodendroglia cells and to neurons. Astrocytes also are connected with each other and with neurons by juctions characterized by wide (250 A) gaps containing opaque gap material and by dense material adhering to the inner surfaces of the plasma membranes. The results suggest a morphological basis for adhesion and intercommunication between all adult derivatives of the embryonic neural tube.

Animals↗

PubMed1981

Astrocyte cell lineage. I. Astrocyte progenitor cells in mouse neopallium.

The astrocyte cell lineage during postnatal development of the neopallium of Swiss mice was studied, using a colony culture assay method in which dissociated neopallial cells form discrete colonies in culture. It was found that immature epithelial-like cells that from type A colonies in culture come primarily from the subventricular zone but also from other regions of the neopallium. In culture, cells of type A colonies from type C colonies consisting of cells, which although still epithelial like, differ morphologically from the type A colony-forming cells. In the presence of dibutyryl cyclic adenosine monophosphate (dBcAMP) the type C colonies form cells rich in glial fibrillary acidic protein (GFAP) and stainable with Cajal's gold chloride sublimate, a stain specific for astrocytes. Therefore, it is proposed that type A colony-forming cells are astrocyte progenitor cells resembling the "pale" cells found in the subventricular zone (Blakemore and Jolly, '72), the "large glioblasts" (Sturrock, '76) and the free subependymal cells (Privat, '70; Paterson et at., '73) in the corpus callosum. The sequence of the lineage, i.e., cells forming type A colonies give rise to cells forming type C colonies which eventually differentiate into astrocytes, takes place in situ as well as in culture. As postnatal development of the neopallium progresses the number of colony-forming cells decreases in the subventricular zone and in other parts of the neopallium. The astrocyte progenitor cells migrate from the subventricular zone to other parts of the neopallium and progress through the lineage of differentiation in all regions of the neopallium.

Animals↗

PubMed2006

TGF-beta1 potentiates astrocytic nitric oxide production by expanding the population of astrocytes that express NOS-2.

Both transforming growth factor-beta1 (TGF-beta1) and nitric oxide synthase-2 (NOS-2) are upregulated under various neuropathological states. Evidence suggests that TGF-beta1 can either attenuate or augment NOS-2 expression, with the prevailing effect dependent on the experimental paradigm employed and the cell-type under study. The purpose of the present study was to determine the effect of TGF-beta1 on astrocytic NOS-2 expression. In purified astrocyte cultures, TGF-beta1 alone did not induce NOS-2 or NO production. However, NO production induced by lipopolysaccharide (LPS) plus IFNgamma was enhanced by TGF-beta1 in a concentration-dependent manner between 10 and 1,000 pg/mL. The presence of IFNgamma was not necessary for this effect to occur, as TGF-beta1 enhanced NO production induced by LPS in a similar fashion. In cultures stimulated with LPS plus IFNgamma, the enhancement of NO production by TGF-beta1 was associated with a corresponding increase in NOS-2 mRNA and protein expression. Interestingly, immunocytochemical assessment of NOS-2 protein expression demonstrated that TGF-beta1 augmented astrocytic NO production, specifically by increasing the pool of astrocytes capable of expressing NOS-2 induced by either LPS (approximately threefold) or LPS plus IFNgamma (approximately sevenfold). In a broader sense, our results suggest that TGF-beta1 recruits a latent population of astrocytes to respond to stimulation by pro-inflammatory mediators.

Animals↗

PubMed1992

Inclusion bodies in cerebral cortical astrocytes: a new change of astrocytes.

A unique pathological finding of astrocytes was observed in the brain of a 20-year-old man who had severe physical and mental retardation. The brain was malformed showing micropolygyria in several cortical areas. A large number of hypertrophic astrocytes with eosinophilic granular substances in their cytoplasm were found throughout the cerebral cortex. Several staining procedures and electron microscopical examinations were carried out on these intracytoplasmic inclusion. It was found that the appearance and staining character of these inclusions were different from other astrocytic changes, especially the Rosenthal fiber, described so far. The authors consider that these inclusion bodies in cerebral cortical astrocytes represent new pathological changes of astrocytes that appear to be associated with malformation of the brain.

Adult↗

PubMed1993

Astrocytic and synaptic response to kindling in hippocampal subfield CA1. II. Synaptogenesis and astrocytic process increases to in vivo kindling.

Astrocytic glia are important for maintaining synaptic function during physiological activity. Recent hypotheses concerning epilepsy suggest a role for astrocytes in the control of neuronal excitability and in pathogenesis. This report provides morphological evidence that the periodic electrical stimulation used in the kindling model of epilepsy induces astrocytic hypertrophy and an increase in shaft synapse density in the CA1 region of the hippocampus. The Schaffer collateral pathway in the stratum radiatum of CA1 of five pairs of rats was kindled in vivo. Control animals received the same number of stimulations at a lower intensity and frequency. The animals were killed 24-48 h after reaching the criterion of five generalized seizures, and the brains were examined by electron microscopy. Kindling produced a 37% and 33% increase in the volume fraction of astrocytic processes in the middle and distal portions, respectively, of the s. radiatum in CA1. In the same tissue, the number (areal density) of shaft synapses was increased 25% in the s. radiatum of animals exhibiting generalized seizures. On the other hand, the areal density of degenerating synapses in both kindled and control animals was low and not significantly different. These results suggest that both synaptogenesis and hypertrophy of astrocytes contribute to an early stage of epileptogenesis when degenerative changes of the sort that might induce gliosis were not prominent in the tissue under study.

Animals↗

PubMed1995

Demonstration of parathyroid hormone-related protein in meninges and its receptor in astrocytes: evidence for a paracrine meningo-astrocytic loop.

In contrast to the nervous and glial tissue of the adult rat brain the meninges are immunoreactive for parathyroid hormone-related protein (PTHrP), a hormone that binds with high affinity to the recently cloned PTH/PTHrP receptor. Accordingly immunoreactivity is found in cultured meningeal cells but not in astrocytes. In contrast, astrocytes but not meningeal cells synthesize the mRNA for the PTHrP receptor shown by reverse transcription of total RNA preparations and subsequent polymerase chain reaction with primers specific for the PTHrP receptor. The expression of the PTH/PTHrP receptor was confirmed by the dose-dependent activation of the adenylate cyclase in astrocytes and the rapid development of cellular processes following on incubation with PTHrP. We conclude that PTHrP secreted by meninges forms a paracrine meningo-astrocytic loop and may cause astrocytic differentiation, possibly involved in the formation of the glial limiting membrane.

Animals↗

PubMed2006

Cyclopamine treatment of human embryonic stem cells followed by culture in human astrocyte medium promotes differentiation into nestin- and GFAP-expressing astrocytic lineage.

Human embryonic stem cells (hESCs) are able to differentiate into various cell types, including neuronal cells and glial cells. However, little information is available regarding astrocyte differentiation. This report describes the differentiation of hESCs into nestin- and GFAP-expressing astrocytes following treatment with cyclopamine, which is an inhibitor of Hedgehog (Hh) signaling, and culturing in human astrocyte medium (HAM). In hESCs, cyclopamine treatment suppressed the expression of Hh signaling molecules, the Hh signaling target gene, and ESC-specific markers. Clyclopamine also induced the differentiation of the cells at the edges of the hESC colonies, and these cells stained positively for the early neural marker nestin. Subsequent culturing in HAM promoted the expression of the astrocyte-specific marker GFAP, and these cells were also nestin-positive. These findings indicate that treatment with cyclopamine followed by culturing in HAM leads to the differentiation of hESCs into nestin- and GFAP-expressing astrocytic lineage.

Astrocytes↗

PubMed2002

Induction of TGF-beta-inducible gene-h3 (betaig-h3) by TGF-beta1 in astrocytes: implications for astrocyte response to brain injury.

Transforming growth factor (TGF)-beta-inducible gene-h3 (betaig-h3) product is a secreted protein that is induced by TGF-beta in several cell types and implicated in various tissue pathologies. The aims of this study were to determine the effect of TGF-beta1 on betaig-h3 expression in cultured astrocytes and to examine whether betaig-h3 is expressed in the brain after traumatic injury. The results showed that betaig-h3 mRNA and protein increased in response to TGF-beta1 in U87 human astrocytoma cells and mouse cortical astrocytes. Treatment with other cytokines, including tumor necrosis factor-alpha and fibroblast growth factor-2, did not enhance the expression of betaig-h3 in astrocytes. betaig-h3 was significantly expressed in reactive astrocytes at the site of a stab wound in the cerebral cortex of adult rats. These results provide an insight into understanding a novel role for betaig-h3 protein in the response of astrocytes to brain injury.

Animals↗

PubMed1998

Astrocytic gap junction blockage and neuronal Ca2+ oscillation in neuron-astrocyte cocultures in vitro.

We have investigated the effects of gap junction inhibitors, octanol, halothane, sodium propionate and lindane, on neuronal periodic Ca2+ transients in neuron-astrocyte coculture systems. Octanol reduced the amplitude and frequency of Ca2+ oscillations in dose-dependent manner. One mM octanol caused a complete disappearance of Ca2+ oscillations. Similar suppressions were obtained by halothane (1 mM) and sodium propionate (25 mM). In contrast, lindane (300 nM) uniquely raised the basal level of [Ca2+], in oscillating neurons as well as the height of apparent amplitude without changes in the frequency. The current results imply that octanol, halothane and sodium propionate might lower the frequency of spontaneous Ca2+ oscillations by blocking the gap junctional communication of neighboring astrocytes and that lindane, though also blocking the gap junctions, might not affect the frequency but reversely increase both the basal [Ca2+]i and the amplitude, probably due to an increase of neuronal [Ins (1.4.5)P3]i. These findings strongly suggest that astrocytes contribute to the generation of periodic neuronal Ca2+ oscillations through astrocytic gap junctional communications and/or other signaling components between astrocytes and neurons.

Animals↗

PubMed2000

Acutely isolated astrocytes as models to probe astrocyte functions.

Neuroscientists have become increasingly aware and accepting of the concept that astrocytes likely have many important functions in the CNS. One limitation in establishing these functions is the usual problem of what constitutes suitable experimental approaches. A major experimental step for functional studies of astrocytes has been the widespread use of primary astrocyte cultures, an approach that Leif Hertz pioneered. However, it is now becoming clear that, building on this work, an experimental paradigm shift is now needed. Namely, to increasingly study preparations corresponding to in situ conditions, such as slices. An alternative experimental system where the cells have some of the technical advantages of primary astrocyte cultures is freshly isolated astrocytes. Recent experiments from our laboratory have shown metabotropic glutamate receptor expression by such cells. Examples are given of how functional receptor studies and channel activity measured by patch clamp electrophysiology can be combined with single cell RT-PCR to define further the receptor or channel type are described to illustrate the uses of such preparations.

Animals↗

PubMedDate not supplied

Importance of astrocytic inactivation of synaptically released glutamate for cell survival in the central nervous system--are astrocytes vulnerable to low intracellular glutamate concentrations?

Multiple levels of neuron-astrocyte interactions do exist at glutamatergic synapses, glial glutamate transporters being involved in most of them. Inactivation of synaptically released glutamate is not only important for the phasic aspect of glutamatergic transmission but also for astrocyte metabolism, which supply neurons with different metabolic precursors, and for cell survival in the central nervous system. Alteration of glutamate transport, which leads to abnormally high extracellular glutamate levels, has been involved in numerous neurodegenerative diseases. There are different ways by which elevated extracellular levels of glutamate can be toxic. Excitotoxic mechanisms, involving overstimulation of glutamate receptors, have been shown to induce the death of neurons and oligodendrocytes, but not of astrocytes. Oxidative glutamate toxicity, which can affect every cell type of the central nervous system, is currently viewed as the consequence of altered cystine transport, leading in turn to reduced glutathione synthesis and oxidative stress. This review summarizes the functional implications of astroglial glutamate transport and the consequences of its alteration. Emphasis is laid on our recent finding that alteration of glutamate transport, by depleting intracellular stores of glutamate, can induce oxidative toxicity in astrocytes. The consequences for the other cell types of the central nervous system are discussed in terms of neuron dependency on astrocytes for glutathione synthesis and therefore oxidative stress protection.

Animals↗

PubMed2007

Differentiated astrocytes acquire sensitivity to hydrogen sulfide that is diminished by the transformation into reactive astrocytes.

Hydrogen sulfide (H2S) enhances the induction of hippocampal long-term potentiation (LTP) and induces calcium waves in astrocytes. Based on these observations, H2S has been proposed to be a synaptic modulator in the brain. Here we show that differentiated astrocytes acquire sensitivity to H2S that is diminished by their transformation into reactive astrocytes. Although sodium hydrosulfide hydrate (NaHS), a donor of H2S, did not increase the intracellular concentration of Ca2+ in progenitors, exposure of progenitors to leukemia inhibitory factor (LIF), which induces differentiation into glial fibrillary acidic protein (GFAP)-positive astrocytes, greatly increased the sensitivity to NaHS. In contrast, epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), dibutyryl cyclic AMP (db cAMP) and interleukin-1beta (IL-1beta) induced the conversion to reactive astrocytes with diminished sensitivity to NaHS. This suppressive effect of EGF on the sensitivity to NaHS was inhibited by cycloheximide, indicating that de novo protein synthesis was required for the suppression of H2S sensitivity.

Animals↗