Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.

Physiology of astroglia

The discovery that transient elevations of calcium concentration occur in astrocytes, and release 'gliotransmitters' which act on neurons and vascular smooth muscle, led to the idea that astrocytes are powerful regulators of neuronal spiking, synaptic plasticity and brain blood flow. These findings were challenged by a second wave of reports that astrocyte calcium transients did not mediate functions attributed to gliotransmitters and were too slow to generate blood flow increases. Remarkably, the tide has now turned again: the most important calcium transients occur in fine astrocyte processes not resolved in earlier studies, and new mechanisms have been discovered by which astrocyte [Ca(2+)]i is raised and exerts its effects. Here we review how this third wave of discoveries has changed our understanding of astrocyte calcium signaling and its consequences for neuronal function.

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Astrocyte Calcium Signaling: The Third Wave

The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer's disease as well as other neurodegenerative diseases.

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Astrocytes: a central element in neurological diseases

Reversible C(6)F(5) transfer takes place between the boron centers in the anion formed by methide abstraction from [MeZr{N(SiMe(3))(2)}(3)] or [Cp(2)ZrMe(2)] (L(n)M-CH(3) in the reaction scheme) by the perfluorinated diborane 1. The solution chemistry of the metallocenium ion pairs formed from 1 and [Cp(2)ZrMe(2)] is correlated with the observed ethylene polymerization behavior of 1 in comparison to the monoborane B(C(6)F(5))(3), the related diborane 1,2-C(6)H(4)[B(C(6)F(5))(2)](2), and the 9,10-diboraanthracene compound 9,10-(C(6)F(5))(2)C(12)B(2)F(8).

Activation of Astrocytes in Neurodegenerative Diseases

Graphene and its derivatives have attracted significant research interest based on their application potential in different fields including biomedicine. However, recent reports from our laboratory and elsewhere have pointed to serious toxic effects of this nanomaterial on cells and organisms. Graphene oxide (GO) was found to be highly thrombogenic in mouse and evoked strong aggregatory response in human platelets. As platelets play a central role in hemostasis and thrombus formation, thrombotoxicity of GO potentially limits its biomedical applications. Surface chemistry of nanomaterials is a critical determinant of biocompatibility, and thus differentially functionalized nanomaterials exhibit varied cellular toxicity. Amine-modified carbon nanotubes have recently been shown to possess cytoprotective action, which was not exhibited by their relatively toxic carboxylated counterparts. We, therefore, evaluated the effect of amine modification of graphene on platelet reactivity. Remarkably, our results revea...

Amine-Modified Graphene: Thrombo-Protective Safer Alternative to Graphene Oxide for Biomedical Applications

Enhanced Ca2+-dependent glutamate release from astrocytes of the BACHD Huntington’s disease mouse model

Carbon nanotubes (CNTs) due to their unique properties have sparked interest for their use in biomedical applications in recent years In particular, the use of CNTs as substrates/scaffolds for neural cell growth has been an area of active research over the past decade CNTs, either native or functionalized with various chemical groups, are biocompatible with neuronal cell adhesion and growth Functionalized CNTs can modulate the neuronal growth in graded manner; positively charged CNTs promoted neurite outgrowth of hippocampal neurons in culture to a greater extent than when these cells were grown on neutral or negatively charged CNTs Conductivity and mechanical properties of CNTs have been shown to affect neuronal morphology as well Other neural cells, such as stem and glial cells, can also be successfully grown on CNT substrates While currently the acute toxicity of CNTs is considered comparable to that of other forms of carbon, the long-term exposures limits need to be established in order to use these materials as neural prosthesis Nonetheless, accumulating data support the use of CNTs as a biocompatible and permissive substrate/scaffold for neural cells and such application holds great potential in biomedicine

Chapter 6 - Carbon nanotubes as substrates/scaffolds for neural cell growth.

Astrocytes possess GPCRs (G-protein-coupled receptors) for neuroactive substances and can respond via these receptors to signals originating from neurons as well as astrocytes. Like many transmembrane proteins, GPCRs exist in a dynamic equilibrium between receptors expressed at the plasma membrane and those present within intracellular trafficking compartments. The characteristics of GPCR trafficking within astrocytes have not been investigated. We therefore monitored the trafficking of recombinant fluorescent protein chimeras of the CB1R (cannabinoid receptor 1) that is thought to be expressed natively in astrocytes. CB1R chimeras displayed a marked punctate intracellular localization when expressed in cultured rat visual cortex astrocytes, an expression pattern reminiscent of native CB1R expression in these cells. Based upon trafficking characteristics, we found the existence of two populations of vesicular CB1R puncta: (i) relatively immobile puncta with movement characteristic of diffusion and (ii) mobile puncta with movement characteristic of active transport along cytoskeletal elements. The predominant direction of active transport is oriented radially to/from the nuclear region, which can be abolished by disruption of the microtubule cytoskeleton. CB1R puncta are localized within intracellular acidic organelles, mainly co-localizing with endocytic compartments. Constitutive trafficking of CB1R to and from the plasma membrane is an energetically costly endeavour whose function is at present unclear in astrocytes. However, given that intracellular CB1Rs can engage cell signalling pathways, it is likely that this process plays an important regulatory role.

Dynamic imaging of cannabinoid receptor 1 vesicular trafficking in cultured astrocytes

Glioblastoma multiforme (GBM) is the most common and aggressive of the primary brain tumors. These tumors express multiple members of the epithelial sodium channel (ENaC)/degenerin (Deg) family and...

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00199.2010

Interaction of ASIC1 and ENaC subunits in human glioma cells and rat astrocytes.

Carbon nanotubes (CNTs) are emerging as nanomaterials with a wide range of biomedical applications, including their potential use for neuroprosthesis (Bekyarova et al., 2005). Thus, an understanding of how CNTs interact with cellular components of the brain is important for engineering of CNT-based devices. The conductive properties and nanoscale features of CNTs make them better suited as an interface with neurons for stimulating and recording neural activity than the conventional bare metal-based electrodes (Keefer et al., 2008). Neurons cultured on CNT substrates showed enhanced neuronal electrical activity (Lovat et al., 2005; Mazzatenta et al., 2007) suggesting an intimate interaction between neurons and CNTs. A recent study by Cellot et al. (2009) investigates the nature of CNT–neuron interactions and proposes a mechanism in which CNTs can boost neuronal activity by providing a shortcut for electrical coupling between somatic and dendritic neuronal compartments. Cellot and colleagues performed wholecell patch clamp experiments on hippocampal and dorsal root ganglia (DRG) neurons cultured on planar CNT substrates deposited onto glass coverslips. They used a pharmacological approach to block neuronal network activity. Cultured neurons were bathed in 6-cyano-7-nitroquinoxaline-2,3-dione and gabazine to inhibit glutamatergic and gamma-amino-butyric acid-ergic synaptic transmission, respectively. This approach allowed for investigation of electrogenic properties of patch-clamped neurons since the endogenous, as opposed to input/synaptically driven, electrical excitability of cells remained intact. To study the contribution of CNTs to neuronal electrical regenerative properties, the whole-cell current-clamped single neurons were stimulated to discharge a train of six spikes/action potentials (APs), at frequencies ranging from 20 to 100 Hz. The post-train changes in neuronal membrane potentials were recorded and analyzed. The integrated membrane potential changes occurring within a 100-ms window starting 50 ms after the last AP of the train were categorized as: (a) after depolarization potential (ADP), (b) neutral response (NR), or (c) after hyperpolarization potential (AHP) (Table 1). Interestingly, hippocampal neurons grown on CNT-coated glass coverslips displayed a distribution of posttrain responses biased towards ADP when compared to the distribution obtained from neurons cultured on plain glass coverslips (Table 1). After depolarization potential represents an electrical excitability based on dendro-somatic electrical coupling arising from summation of dendritic Ca2+

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William Lee

Papers

Enhanced Ca2+-dependent glutamate release from astrocytes of the BACHD Huntington’s disease mouse model

Chapter 6 - Carbon nanotubes as substrates/scaffolds for neural cell growth.

Dynamic imaging of cannabinoid receptor 1 vesicular trafficking in cultured astrocytes

Interaction of ASIC1 and ENaC subunits in human glioma cells and rat astrocytes.

Wiring neurons with carbon nanotubes.