Glial Cell Function Research Articles

OS3.4 Effect of bevacizumab on the morphology and function of neurons and glial cells

OS3.4 Effect of bevacizumab on the morphology and function of neurons and glial cells

Fluid levity of the cell: Role of membrane lipid architecture in genetic sphingolipidoses.

Sphingolipidoses arise from inherited loss of function of key enzymes regulating the sphingolipid (SL) metabolism and the accumulation of large quantities of these lipids in affected cells. Most frequently, toxicity is manifested in the nervous system, where survival and function of neurons and glial cells are most affected. Although detailed information is available on neuroglial alterations during terminal stages of the disease, the initial pathogenic mechanisms triggering neuropathology are largely unclear. Because they are key components of biological membranes, changes in the local concentration of SLs are likely to impact the organization of membrane domains and functions. This Commentary proposes that SL toxicity involves initial defects in the integrity of lipid domains, membrane fluidity, and membrane bending, leading to membrane deformation and deregulation of cell signaling and function. Understanding how SLs alter membrane architecture may provide breakthroughs for more efficient treatment of sphingolipidoses. © 2016 Wiley Periodicals, Inc.

LPA1 Mediates Antidepressant-Induced ERK1/2 Signaling and Protection from Oxidative Stress in Glial Cells.

Antidepressants have been shown to affect glial cell functions and intracellular signaling through mechanisms that are still not completely understood. In the present study, we provide evidence that in glial cells the lysophosphatidic acid (LPA) receptor LPA1 mediates antidepressant-induced growth factor receptor transactivation, ERK1/2 signaling, and protection from oxidative stress. Thus, in C6 glioma cells and rat cortical astrocytes, ERK1/2 activation induced by either amitriptyline or mianserin was antagonized by Ki16425 and VPC 12249 (S), which block LPA1 and LPA3 receptors, and by AM966, which selectively blocks LPA1 Cell depletion of LPA1 with siRNA treatment markedly reduced antidepressant- and LPA-induced ERK1/2 phosphorylation. LPA1 blockade prevented antidepressant-induced phosphorylation of the transcription factors CREB and Elk-1. Antidepressants and LPA signaling to ERK1/2 was abrogated by cell treatment with pertussis toxin and by the inhibition of fibroblast growth factor (FGF) receptor (FGF-R) and platelet-derived growth factor receptor (PDGF-R) tyrosine kinases. Both Ki16425 and AM966 suppressed antidepressant-induced phosphorylation of FGF-R. Moreover, blockade of LPA1 or inhibition of FGF-R and PDGF-R activities prevented antidepressant-stimulated Akt and GSK-3β phosphorylations. Mianserin protected C6 glioma cells and astrocytes from apoptotic cell death induced by H2O2, as indicated by increased cell viability, decreased expression of cleaved caspase 3, reduced cleavage of poly-ADP ribose polymerase and inhibition of DNA fragmentation. The protective effects of mianserin were antagonized by AM966. These data indicate that LPA1 constitutes a novel molecular target of the regulatory actions of tricyclic and tetracyclic antidepressants in glial cells.

The crucial role of Erk2 in demyelinating inflammation in the central nervous system.

BackgroundBrain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation.MethodsWe used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes.ResultsFirst, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3–4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2.ConclusionsOur results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of distinct demyelinating diseases.

Mechanisms of Aβ Clearance and Degradation by Glial Cells.

Glial cells have a variety of functions in the brain, ranging from immune defense against external and endogenous hazardous stimuli, regulation of synaptic formation, calcium homeostasis, and metabolic support for neurons. Their dysregulation can contribute to the development of neurodegenerative disorders, including Alzheimer’s disease (AD). One of the most important functions of glial cells in AD is the regulation of Amyloid-β (Aβ) levels in the brain. Microglia and astrocytes have been reported to play a central role as moderators of Aβ clearance and degradation. The mechanisms of Aβ degradation by glial cells include the production of proteases, including neprilysin, the insulin degrading enzyme, and the endothelin-converting enzymes, able to hydrolyse Aβ at different cleavage sites. Besides these enzymes, other proteases have been described to have some role in Aβ elimination, such as plasminogen activators, angiotensin-converting enzyme, and matrix metalloproteinases. Other relevant mediators that are released by glial cells are extracellular chaperones, involved in the clearance of Aβ alone or in association with receptors/transporters that facilitate their exit to the blood circulation. These include apolipoproteins, α2macroglobulin, and α1-antichymotrypsin. Finally, astrocytes and microglia have an essential role in phagocytosing Aβ, in many cases via a number of receptors that are expressed on their surface. In this review, we examine all of these mechanisms, providing an update on the latest research in this field.

CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury.

Neurodegeneration in the adult mammalian central nervous system (CNS) is fundamentally accelerated by its intrinsic neuronal mechanisms, including its poor regenerative capacity and potent extrinsic inhibitory factors. Thus, the treatment of neurodegenerative diseases faces many obstacles. The degenerative processes, consisting of axonal/dendritic structural disruption, abnormal axonal transport, release of extracellular factors, and inflammation, are often controlled by the cytoskeleton. From this perspective, regulators of the cytoskeleton could potentially be a therapeutic target for neurodegenerative diseases and CNS injury. Collapsin response mediator proteins (CRMPs) are known to regulate the assembly of cytoskeletal proteins in neurons, as well as control axonal growth and neural circuit formation. Recent studies have provided some novel insights into the roles of CRMPs in several inhibitory signaling pathways of neurodegeneration, in addition to its functions in neurological disorders and CNS repair. Here, we summarize the roles of CRMPs in axon regeneration and its emerging functions in non-neuronal cells, especially in inflammatory responses. We also discuss the direct and indirect targeting of CRMPs as a novel therapeutic strategy for neurological diseases.

Glial biomarkers in human central nervous system disease.

There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment. For example, imaging studies of the CNS enable localization and characterization of anatomical lesions without the need to isolate tissue for biopsy. Many biomarkers of disease pathology in the CNS involve assays of glial cell function and/or response to injury. Each major glia subtype (oligodendroglia, astroglia and microglia) are connected to a number of important and useful biomarkers. Here, we describe current and emerging glial based biomarker approaches for acute CNS injury and the major categories of chronic nervous system dysfunction including neurodegenerative, neuropsychiatric, neoplastic, and autoimmune disorders of the CNS. These descriptions are highlighted in the context of how biomarkers are employed to better understand the role of glia in human CNS disease and in the development of novel therapeutic treatments. GLIA 2016;64:1755-1771.

Proteomic profiling reveals dopaminergic regulation of progenitor cell functions of goldfish radial glial cells in vitro

Radial glial cells (RGCs) are stem-like cells found in the developing and adult central nervous system. They function as both a scaffold to guide neuron migration and as progenitor cells that support neurogenesis. Our previous study revealed a close anatomical relationship between dopamine neurons and RGCs in the telencephalon of female goldfish. In this study, label-free proteomics was used to identify the proteins in a primary RGC culture and to determine the proteome response to the selective dopamine D1 receptor agonist SKF 38393 (10μM), in order to better understand dopaminergic regulation of RGCs. A total of 689 unique proteins were identified in the RGCs and these were classified into biological and pathological pathways. Proteins such as nucleolin (6.9-fold) and ependymin related protein 1 (4.9-fold) were increased in abundance while proteins triosephosphate isomerase (10-fold) and phosphoglycerate dehydrogenase (5-fold) were decreased in abundance. Pathway analysis revealed that proteins that consistently changed in abundance across biological replicates were related to small molecules such as ATP, lipids and steroids, hormones, glucose, cyclic AMP and Ca2+. Sub-network enrichment analysis suggested that estrogen receptor signaling, among other transcription factors, is regulated by D1 receptor activation. This suggests that these signaling pathways are correlated to dopaminergic regulation of radial glial cell functions. Most proteins down-regulated by SKF 38393 were involved in cell cycle/proliferation, growth, death, and survival, which suggests that dopamine inhibits the progenitor-related processes of radial glial cells. Examples of differently expressed proteins including triosephosphate isomerase, nucleolin, phosphoglycerate dehydrogenase and capping protein (actin filament) muscle Z-line beta were validated by qPCR and western blot, which were consistent with MS/MS data in the direction of change. This is the first study to characterize the RGC proteome on a large scale in a vertebrate species. These data provide novel insight into glial protein networks that are associated with neuroendocrine function and neurogenesis in the teleost brain. Biological significanceWhile the role of radial glial cells in organizing brain structure and neurogenesis has been well studied, protein profiling experiments in this unique cell type has not been conducted. This study is the first to profile the proteome of goldfish radial glial cells in culture and to study the regulation of progenitor functions of radial glial cells by the neurotransmitter dopamine. This study provides the foundation for molecular network analysis in fish radial glial cells, and identifies cellular processes and signaling pathways in these cells with roles in neurogenesis and neuroendocrine function. Lastly, this study begins to characterize signatures and biomarkers for specific neuroendocrine and neurogenesis disruptors.

Glia, sympathetic activity and cardiovascular disease.

New Findings What is the topic of this review? In this review, we discuss recent findings that provide a novel insight into the mechanisms that link glial cell function with the pathogenesis of cardiovascular disease, including systemic arterial hypertension and chronic heart failure. What advances does it highlight? We discuss how glial cells may influence central presympathetic circuits, leading to maladaptive and detrimental increases in sympathetic activity and contributing to the development and progression of cardiovascular disease. Increased activity of the sympathetic nervous system is associated with the development of cardiovascular disease and may contribute to its progression. Vasomotor and cardiac sympathetic activities are generated by the neuronal circuits located in the hypothalamus and the brainstem. These neuronal networks receive multiple inputs from the periphery and other parts of the CNS and, at a local level, may be influenced by their non‐neuronal neighbours, in particular glial cells. In this review, we discuss recent experimental evidence suggesting that astrocytes and microglial cells are able to modulate the activity of sympathoexcitatory neural networks in disparate physiological and pathophysiological conditions. We focus on the chemosensory properties of astrocytes residing in the rostral ventrolateral medulla oblongata and discuss signalling mechanisms leading to glial activation during brain hypoxia and inflammation. Alterations in these mechanisms may lead to heightened activity of sympathoexcitatory CNS circuits and contribute to maladaptive and detrimental increases in sympathetic tone associated with systemic arterial hypertension and chronic heart failure.

Editorial: Glial Cells: Managers of Neuro-Immunity.

Editorial: Glial Cells: Managers of Neuro-Immunity.

Impact of Plant-Derived Flavonoids on Neurodegenerative Diseases.

Neurodegenerative disorders have a common characteristic that is the involvement of different cell types, typically the reactivity of astrocytes and microglia, characterizing gliosis, which in turn contributes to the neuronal dysfunction and or death. Flavonoids are secondary metabolites of plant origin widely investigated at present and represent one of the most important and diversified among natural products phenolic groups. Several biological activities are attributed to this class of polyphenols, such as antitumor activity, antioxidant, antiviral, and anti-inflammatory, among others, which give significant pharmacological importance. Our group have observed that flavonoids derived from Brazilian plants Dimorphandra mollis Bent., Croton betulaster Müll. Arg., e Poincianella pyramidalis Tul., botanical synonymous Caesalpinia pyramidalis Tul. also elicit a broad spectrum of responses in astrocytes and neurons in culture as activation of astrocytes and microglia, astrocyte associated protection of neuronal progenitor cells, neuronal differentiation and neuritogenesis. It was observed the flavonoids also induced neuronal differentiation of mouse embryonic stem cells and human pluripotent stem cells. Moreover, with the objective of seeking preclinical pharmacological evidence of these molecules, in order to assess its future use in the treatment of neurodegenerative disorders, we have evaluated the effects of flavonoids in preclinical in vitro models of neuroinflammation associated with Parkinson's disease and glutamate toxicity associated with ischemia. In particular, our efforts have been directed to identify mechanisms involved in the changes in viability, morphology, and glial cell function induced by flavonoids in cultures of glial cells and neuronal cells alone or in interactions and clarify the relation with their neuroprotective and morphogetic effects.

Astrocytes and Microglia and Their Potential Link with Autism Spectrum Disorders.

The cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not fully understood although it has been shown that various genetic and environmental factors contribute to their etiology. As increasing evidence indicates that astrocytes and microglial cells play a major role in synapse maturation and function, and there is evidence of deficits in glial cell functions in ASDs, one current hypothesis is that glial dysfunctions directly contribute to their pathophysiology. The aim of this review is to summarize microglia and astrocyte functions in synapse development and their contributions to ASDs.

The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures.

BackgroundBAF312 (Siponimod) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. This drug is currently undergoing clinical trials for the treatment of secondary progressive multiple sclerosis (MS). Here, we investigated the effects of BAF312 on isolated astrocyte and microglia cultures as well as in slice culture models of demyelination.MethodsMouse and human astrocytes were treated with S1PR modulators and changes in the levels of pERK, pAkt, and calcium signalling as well as S1PR1 internalization and cytokine levels was investigated using Western blotting, immunochemistry, ELISA and confocal microscopy. Organotypic slice cultures were prepared from the cerebellum of 10-day-old mice and treated with lysophosphatidylcholine (LPC), psychosine and/or S1PR modulators, and changes in myelination states were measured by fluorescence of myelin basic protein and neurofilament H.ResultsBAF312 treatment of human and mouse astrocytes activated pERK, pAKT and Ca2+ signalling as well as inducing S1PR1 internalization. Notably, activation of S1PR1 increased pERK and pAKT in mouse astrocytes while both S1PR1 and S1PR3 equally increased pERK and pAKT in human astrocytes, suggesting that the coupling of S1PR1 and S1PR3 to pERK and pAKT differ in mouse and human astrocytes. We also observed that BAF312 moderately attenuated lipopolysaccharide (LPS)- or TNFα/IL17-induced levels of IL6 in both astrocyte and microglia cell cultures. In organotypic slice cultures, BAF312 reduced LPC-induced levels of IL6 and attenuated LPC-mediated demyelination. We have shown previously that the toxic lipid metabolite psychosine induces demyelination in organotypic slice cultures, without altering the levels of cytokines, such as IL6. Importantly, psychosine-induced demyelination was also attenuated by BAF312.ConclusionsOverall, this study suggests that BAF312 can modulate glial cell function and attenuate demyelination, highlighting this drug as a further potential therapy in demyelinating disorders, beyond MS.

Fetal Alcohol Spectrum Disorders: An Overview from the Glia Perspective.

Alcohol consumption during pregnancy can produce a variety of central nervous system (CNS) abnormalities in the offspring resulting in a broad spectrum of cognitive and behavioral impairments that constitute the most severe and long-lasting effects observed in fetal alcohol spectrum disorders (FASD). Alcohol-induced abnormalities in glial cells have been suspected of contributing to the adverse effects of alcohol on the developing brain for several years, although much research still needs to be done to causally link the effects of alcohol on specific brain structures and behavior to alterations in glial cell development and function. Damage to radial glia due to prenatal alcohol exposure may underlie observations of abnormal neuronal and glial migration in humans with Fetal Alcohol Syndrome (FAS), as well as primate and rodent models of FAS. A reduction in cell number and altered development has been reported for several glial cell types in animal models of FAS. In utero alcohol exposure can cause microencephaly when alcohol exposure occurs during the brain growth spurt a period characterized by rapid astrocyte proliferation and maturation; since astrocytes are the most abundant cells in the brain, microenchephaly may be caused by reduced astrocyte proliferation or survival, as observed in in vitro and in vivo studies. Delayed oligodendrocyte development and increased oligodendrocyte precursor apoptosis has also been reported in experimental models of FASD, which may be linked to altered myelination/white matter integrity found in FASD children. Children with FAS exhibit hypoplasia of the corpus callosum and anterior commissure, two areas requiring guidance from glial cells and proper maturation of oligodendrocytes. Finally, developmental alcohol exposure disrupts microglial function and induces microglial apoptosis; given the role of microglia in synaptic pruning during brain development, the effects of alcohol on microglia may be involved in the abnormal brain plasticity reported in FASD. The consequences of prenatal alcohol exposure on glial cells, including radial glia and other transient glial structures present in the developing brain, astrocytes, oligodendrocytes and their precursors, and microglia contributes to abnormal neuronal development, reduced neuron survival and disrupted brain architecture and connectivity. This review highlights the CNS structural abnormalities caused by in utero alcohol exposure and outlines which abnormalities are likely mediated by alcohol effects on glial cell development and function.

Adhesion GPCRs as Novel Actors in Neural and Glial Cell Functions: From Synaptogenesis to Myelination.

Adhesion G-protein-coupled receptors (aGPCRs) are emerging as key regulators of nervous system development and health. aGPCRs can regulate many aspects of neural development, including cell signaling, cell-cell and cell-matrix interactions, and, potentially, mechanosensation. Here, we specifically focus on the roles of several aGPCRs in synapse biology, dendritogenesis, and myelinating glial cell development. The lessons learned from these examples may be extrapolated to other contexts in the nervous system and beyond.

Tissue engineering cell-based bioelectronics

Event Abstract Back to Event Tissue engineering cell-based bioelectronics Ulises Aregueta Robles1, Khoon S. Lim2, Penny J. Martens1, Nigel H. Lovell1, Laura A. Poole-Warren1 and Rylie A. Green1 1 University of NSW, Graduate School of Biomedical Engineering, Australia 2 University of Otago, Department of Orthopaedic Surgery & Musculoskeletal Medicine, New Zealand Tissue engineered electrodes aim to deliver a living cellular layer to interface bionic devices with target tissue by establishing synaptic connections between the electrode and target nerve. A significant challenge in developing this technology is to engineer a hydrogel carrier that can support growth and function of complex neuronal networks. To provide an appropriate neural cell niche, it is desirable to have not only neural cells, but supporting glia within the hydrogel carrier. It has been hypothesized that a hydrogel tailored to support glial cell survival and function will be able to support neuronal development. Poly(vinyl alcohol) functionalized with tyramine (PVA-Tyr) is a hydrogel system that supports covalent incorporation of non-modified tyrosine rich proteins, mimicking the biological environment and enabling 3D cell encapsulation[1]. PVA-Tyr has been co-polymerized with gelatin and sericin and the resulting gel supported glial cell growth. However, development of an appropriate system for use at the neural interface requires tailoring of the hydrogel properties such that (i) the mechanical stiffness is similar to that of neural tissues, and (ii) the hydrogel degradation rate is matched to cell maturation and development of extracellular matrix (ECM). Since physical and mechanical properties of PVA relate to the percent polymer[2], the aim of this research was to investigate the impact of varying the hydrogel macromer percentage on the mechanical stiffness and physical degradation of PVA-Tyr/sericin/gelatin (PVA-T/S/G), and the subsequent impact on glial cell survival and development. Two variants of PVA-T/S/G, 10 wt% and 5 wt%, were developed and used to encapsulate peripheral glia (Schwann cells). PVA-Tyr (8 or 3 wt%) hydrogel was crosslinked with gelatin (1 wt%) and sericin (1 wt%) as previously described[1]. Schwann cells (SC, SCL4.1/F7) were encapsulated at 107 cells/mL. Cellular viability was tracked by live/dead staining. Hydrogel stiffness was measured by compression tests (50 N load cell, 0.5 mm/min, 5 - 15% strain). Cells were immunostained for S100 (mature SC marker), laminin and collagen-IV (ECM deposition) and bisbenzimide (nuclei). Hydrogel degradation was tracked to the point of reverse gelation. All the tests were performed at 0, 1, 5 and 10 days. Cells remained viable at all the time points. Compression tests showed that PVA-T/S/G at 10 wt% had a mean compressive modulus of 41.5 kPa at Day 0, which reduced to 0.5 kPa by Day 10. The corresponding compressive modulus for the 5 wt% hydrogel was 6.1 kPa at Day 0 and 0.6 kPa at Day 10. SCs interact preferably with substrates having a stiffness from 1 - 10 kPa[3], where they adopt bipolar morphologies that support nerve guidance and repair in vivo[4]. In both systems at 5 days post-encapsulation bipolar morphologies were evident (see Figure 1), but were more prolific in the 5 wt% hydrogels. Presence of laminin and collagen-IV was also observed by immunostaining. Expression of these molecules is an indication of mature and functional SCs[5]. Both systems were shown to be completely degraded at 15 ± 3 days. While these different hydrogels provide similar support to SCs the ability to vary the hydrogel stiffness is expected to be key to the development of a complex living electrode with both glia and neuronal cell types, as previously proposed[6]. Figure 1. SC embedded in 10% (left) and 5%(right) PVA-T/S/G hydrogel at 5 days in culture. Nuclei (blue). Collagen-IV (green). Scale bar = 50 μm SCs were able to adopt bipolar morphologies and express ECM required for neuronal development with 5 and 10 wt% hydrogels. These outcomes suggest that the PVA-T/S/G hydrogels provide physical and biochemical support for SC survival and maturation. Future studies will assess the capacity of SCs to support neuronal survival within PVA-T/S/G. Australian Research Council (ARC) through its Special Research Initiative (SRI) in Bionic Vision Science and Technology grant to Bionic Vision Australia (BVA)

The Effect of Chronic Alcohol Abuse on the Benzodiazepine Receptor System in Various Areas of the Human Brain

Objective: Alcohol abuse induces neuroadaptive changes in the functioning of neurotransmitter systems in the brain. Decrease of GABAergic neurotransmission found in alcoholics and persons with a high risk of alcohol dependence. Benzodiazepine receptor (BzDR) is allosterical modulatory site on GABA type A receptor complex (GABAAR), that modulate GABAergic function and may be important in mechanisms regulating the excitability of the brain processes involved in the alcohol addiction. The purpose of this study was to investigate the effects of chronic alcohol abuse on the BzDR in various areas of the human brain. Materials and Methods: Investigation of BzDR properties were studied in synaptosomal and mitochondrial membrane fractions from different brain areas of alcohol abused patients and non-alcoholic persons by radioreceptor assay with using selective ligands: [3H] flunitrazepam and [3H] PK-11195. Brain samples obtained at autopsy urgent. In total 126 samples of human brain areas were obtained to study radioreceptor binding, including a study group and control group. Results: Comparative study of kinetic parameters (Kd, Bmax) of [3H] flunitrazepam and [3H] PK-11195 binding with membrane fractions in studding brain samples was showed that affinity of BzDR was decreased and capacity increased in different areas of human brain under influence of alcohol abuse. More alters of synaptic BzDR “central” type (CBR) appeared in prefrontal cortex, mitochondrial BzDR “peripheral” type (PBR) – in n.caudatus and cerebella cortex. These results showed that alcohol addiction induce more expressive alterations in PBR than CBR in the brain structures that agree with maintaining function of glial cells in CNS under influence of different toxic factors. Conclusion: Chronic exposure to ethanol results in harmful effects on the human brain: causing nonuniform adaptive changes of BzDR in various areas of the brain, which can modulate GABAAR and reduce neuromediation GABA in various areas of the brain which can cause alcohol addiction. Graphical Abstract: Alcohol abuse induces neuroadaptive alters of benzodiazepine receptor system in various areas of the brain in patients with alcoholism that can modulate GABAAR and mediation of GABA in the brain, which can cause alcohol addiction.

Glial Cells and Integrity of the Nervous System.

Today, there is enormous progress in understanding the function of glial cells, including astroglia, oligodendroglia, Schwann cells, and microglia. Around 150years ago, glia were viewed as a glue among neurons. During the course of the twentieth century, microglia were discovered and neuroscientists' views evolved toward considering glia only as auxiliary cells of neurons. However, over the last two to three decades, glial cells' importance has been reconsidered because of the evidence on their involvement in defining central nervous system architecture, brain metabolism, the survival of neurons, development and modulation of synaptic transmission, propagation of nerve impulses, and many other physiological functions. Furthermore, increasing evidence shows that glia are involved in the mechanisms of a broad spectrum of pathologies of the nervous system, including some psychiatric diseases, epilepsy, and neurodegenerative diseases to mention a few. It appears safe to say that no neurological disease can be understood without considering neuron-glia crosstalk. Thus, this book aims to show different roles played by glia in the healthy and diseased nervous system, highlighting some of their properties while considering that the various glial cell types are essential components not only for cell function and integration among neurons, but also for the emergence of important brain homeostasis.

Pharmacological Tools to Study the Role of Astrocytes in Neural Network Functions.

Despite that astrocytes and microglia do not communicate by electrical impulses, they can efficiently communicate among them, with each other and with neurons, to participate in complex neural functions requiring broad cell-communication and long-lasting regulation of brain function. Glial cells express many receptors in common with neurons; secrete gliotransmitters as well as neurotrophic and neuroinflammatory factors, which allow them to modulate synaptic transmission and neural excitability. All these properties allow glial cells to influence the activity of neuronal networks. Thus, the incorporation of glial cell function into the understanding of nervous system dynamics will provide a more accurate view of brain function. Our current knowledge of glial cell biology is providing us with experimental tools to explore their participation in neural network modulation. In this chapter, we review some of the classical, as well as some recent, pharmacological tools developed for the study of astrocyte's influence in neural function. We also provide some examples of the use of these pharmacological agents to understand the role of astrocytes in neural network function and dysfunction.

Micronuclei Induction and Neurotoxic Effect in C6 Glioma Cells Exposed to Low Concentrations of Diazinon, an Organophosphorus Compound

Background: The presence of doses of diazinon far lower than IC50 cholinesterase activity was reported in plasma of pregnant women and newborns living in agricultural areas. Objective: In the current study, we investigated the possibility of neurotoxicity induction by exposing cultured gliotypic C6 cells to a similar range of concentrations, for 24 h, at 37°C. Materials and methods: Confluent C6 cellswere exposed to diazinon (DZN) at concentrations from 200ng/L to 0.002ng/L. The maintenance of confluence, the induction of micronuclei and the expression of molecules related to the cholinergic system were verified, by morphological, biochemical and immunohistochemical methods, in order to check the effects of the altered modulation of the cholinergic signal on glial-like cells. Results: The exposure to 0.002ng/L showed significant effecton micronuclei occurrence since the exposure to 0.002ng/L, while the inhibition on butyrylcholinesterase activity showed significant variations starting from the exposure to 0.2ng/L up to 200ng/L. Acetylcholinesterase activity was significantly inhibited only by the exposure to 200ng/L. The immunohistochemical localization of choline acetyltransferase and fibronectin showed dramatic variation only in C6 cells exposed to 200ng/L. Conclusion: The low doses of DZN investigated affect the investigated features of glial-like cells, mainly starting from the 0.2ng/L dose, while the effects on AChE activity and ChAT and fibronectin-immuorectivity were clearly exerted in cell cultures exposed to 200ng/L. Collectively, these findings translated to the in vivo functions of glial cells indicate that exposure to doses that are nontoxic to adult organisms may weaken the brain defense and functions of glial cells through an AChE-mediated mechanisms.