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      Gliotransmitter Release from Astrocytes: Functional, Developmental, and Pathological Implications in the Brain

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          Abstract

          Astrocytes comprise a large population of cells in the brain and are important partners to neighboring neurons, vascular cells, and other glial cells. Astrocytes not only form a scaffold for other cells, but also extend foot processes around the capillaries to maintain the blood–brain barrier. Thus, environmental chemicals that exist in the blood stream could have potentially harmful effects on the physiological function of astrocytes. Although astrocytes are not electrically excitable, they have been shown to function as active participants in the development of neural circuits and synaptic activity. Astrocytes respond to neurotransmitters and contribute to synaptic information processing by releasing chemical transmitters called “gliotransmitters.” State-of-the-art optical imaging techniques enable us to clarify how neurotransmitters elicit the release of various gliotransmitters, including glutamate, D-serine, and ATP. Moreover, recent studies have demonstrated that the disruption of gliotransmission results in neuronal dysfunction and abnormal behaviors in animal models. In this review, we focus on the latest technical approaches to clarify the molecular mechanisms of gliotransmitter exocytosis, and discuss the possibility that exposure to environmental chemicals could alter gliotransmission and cause neurodevelopmental disorders.

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          Astrocyte-endothelial interactions at the blood-brain barrier.

          The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.
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            Diversity of astrocyte functions and phenotypes in neural circuits.

            Astrocytes tile the entire CNS. They are vital for neural circuit function, but have traditionally been viewed as simple, homogenous cells that serve the same essential supportive roles everywhere. Here, we summarize breakthroughs that instead indicate that astrocytes represent a population of complex and functionally diverse cells. Physiological diversity of astrocytes is apparent between different brain circuits and microcircuits, and individual astrocytes display diverse signaling in subcellular compartments. With respect to injury and disease, astrocytes undergo diverse phenotypic changes that may be protective or causative with regard to pathology in a context-dependent manner. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit-specific roles in health and disease.
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              Tripartite synapses: glia, the unacknowledged partner.

              According to the classical view of the nervous system, the numerically superior glial cells have inferior roles in that they provide an ideal environment for neuronal-cell function. However, there is a wave of new information suggesting that glia are intimately involved in the active control of neuronal activity and synaptic neurotransmission. Recent evidence shows that glia respond to neuronal activity with an elevation of their internal Ca2+ concentration, which triggers the release of chemical transmitters from glia themselves and, in turn, causes feedback regulation of neuronal activity and synaptic strength. In view of these new insights, this article suggests that perisynaptic Schwann cells and synaptically associated astrocytes should be viewed as integral modulatory elements of tripartite synapses.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                12 January 2016
                2015
                : 9
                : 499
                Affiliations
                Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo Tokyo, Japan
                Author notes

                Edited by: Fumihiko Maekawa, National Institute for Environmental Studies, Japan

                Reviewed by: Robert Pawlak, University of Exeter, UK; Nobuo Nagai, Nagahama Institute of Bio-Science and Technology, Japan

                *Correspondence: Takashi Tsuboi takatsuboi@ 123456bio.c.u-tokyo.ac.jp

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2015.00499
                4709856
                26793048
                2bfdcef6-e842-4e17-855a-07239df9f403
                Copyright © 2016 Harada, Kamiya and Tsuboi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 November 2015
                : 15 December 2015
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 99, Pages: 9, Words: 6600
                Categories
                Endocrinology
                Mini Review

                Neurosciences
                astrocytes,exocytosis,glial cell,gliotransmitter,neurodevelopmental disorders,optical imaging,synaptic activity

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