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Physiology of Astroglia: Channels, Receptors, Transporters, Ion Signaling and Gliotransmission

Authors:
Alexei Verkhratsky at The University of Manchester
Alexei Verkhratsky
Vladimir Parpura at Zhejiang Chinese Medical University
Vladimir Parpura
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Abstract

Astrocytes can be defined as the glia inhabiting the nervous system with the main function in the maintenance of nervous tissue homeostasis. Classified into several types according to their morphological appearance, many of astrocytes form a reticular structure known as astroglial syncytium, owing to their coupling via intercellular channels organized into gap junctions. Not only do astrocytes establish such homocellular contacts, but they also engage in intimate heterocellular interactions with neurons, most notably at synaptic sites. As synaptic structures house the very core of information transfer and processing in the nervous system, astroglial perisynaptic positioning assures that these glial cells can nourish neurons and establish bidirectional communication with them, functions outlined in the concepts of the astrocytic cradle and multi-partite synapse, respectively. Astrocytes possess a rich assortment of ligand receptors, ion and water channels, and ion and ligand transporters, which collectively contribute to astrocytic control of homeostasis and excitability. Astroglia control glutamate and adenosine homeostasis to exert modulatory actions affecting the real-time operation of synapses. Fluctuations of intracellular calcium can lead to the release of various chemical transmitters from astrocytes through a process termed gliotransmission. Sodium fluctuations are closely associated to those of calcium with both dynamic events interfacing signaling and metabolism. Astrocytes appear fully integrated into the brain cellular circuitry, being an indispensable part of neural networks.
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Physiology of Astroglia
Channels, Receptors, Transporters,
Ion Signaling and Gliotransmission
Alexei Verkhratsky
Vladimir Parpura
Series Editor: Michael Dean, Ph.D.
VERKHRATSKY • PARPURA PH YSIOLOGY OF ASTROGLIA
MORGAN&CLAYPOOL
Physiology of Astroglia
Alexei Verkhratsky, M.D., Ph.D., D.Sc., M.A.E., M.L., M.R.A.N.F.,
e University of Manchester, Manchester, U.K.; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Vladimir Parpura, M.D., Ph.D., M.A.E., Department of Neurobiology, Center for Glial Biology in Medicine,
Atomic Force Microscopy & Nanotechnology Laboratories, Civitan International Research Center,
Evelyn F. McKnight Brain Institute, University of Alabama, Birmingham, AL, U.S.A.;
Department of Biotechnology, University of Rijeka, Croatia
Astrocytes can be dened as the glia inhabiting the nervous system with the main function in the maintenance
of nervous tissue homeostasis. Classied into several types according to their morphological appearance, many
of astrocytes form a reticular structure known as astroglial syncytium, owing to their coupling via intercellular
channels organized into gap junctions. Not only do astrocytes establish such homocellular contacts, but they
also engage in intimate heterocellular interactions with neurons, most notably at synaptic sites. As synaptic
structures house the very core of information transfer and processing in the nervous system, astroglial perisyn-
aptic positioning assures that these glial cells can nourish neurons and establish bidirectional communication
with them, functions outlined in the concepts of the astrocytic cradle and multi-partite synapse, respectively.
Astrocytes possess a rich assortment of ligand receptors, ion and water channels, and ion and ligand transport-
ers, which collectively contribute to astrocytic control of homeostasis and excitability. Astroglia control glu-
tamate and adenosine homeostasis to exert modulatory actions aecting the real-time operation of synapses.
Fluctuations of intracellular calcium can lead to the release of various chemical transmitters from astrocytes
through a process termed gliotransmission. Sodium uctuations are closely associated to those of calcium with
both dynamic events interfacing signaling and metabolism. Astrocytes appear fully integrated into the brain
cellular circuitry, being an indispensable part of neural networks.
is volume is a printed version of a work that appears in the Colloquium
Digital Library of Life
Sciences. Colloquium titles cover all of cell and molecular biology and biomedicine, includ-
ing the neurosciences, from the advancedundergraduate and graduate level up to the post-
graduate and practicing researcher level. ey oer concise, original presentations of important
research and development topics, published quickly, in digital
and print formats. For more
information, visit www.morganclaypool.com
Series Editors: Alexei Verkhratsky & Vladimir Parpura Series Editors: Alexei Verkhratsky & Vladimir Parpura
ISSN 2375-9933
Colloquium series on
neuroglia in Biology and mediCine
from physiology to disease
MORGAN & CLAYPOOL LIFE SCIENCES
www.morganclaypool.com
ISBN: 978-1-61504-672-0
9 781615 046720
90000
life sciences
MORGAN & CLAYPOOL LIFE SCIENCES
life sciences
Colloquium series on
neuroglia in Biology and mediCine
from physiology to disease
Physiology of Astroglia
Channels, Receptors, Transporters,
Ion Signaling and Gliotransmission
Alexei Verkhratsky
Vladimir Parpura
Series Editor: Michael Dean, Ph.D.
VERKHRATSKY • PARPURA PH YSIOLOGY OF ASTROGLIA
MORGAN&CLAYPOOL
Physiology of Astroglia
Alexei Verkhratsky, M.D., Ph.D., D.Sc., M.A.E., M.L., M.R.A.N.F.,
e University of Manchester, Manchester, U.K.; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Vladimir Parpura, M.D., Ph.D., M.A.E., Department of Neurobiology, Center for Glial Biology in Medicine,
Atomic Force Microscopy & Nanotechnology Laboratories, Civitan International Research Center,
Evelyn F. McKnight Brain Institute, University of Alabama, Birmingham, AL, U.S.A.;
Department of Biotechnology, University of Rijeka, Croatia
Astrocytes can be dened as the glia inhabiting the nervous system with the main function in the maintenance
of nervous tissue homeostasis. Classied into several types according to their morphological appearance, many
of astrocytes form a reticular structure known as astroglial syncytium, owing to their coupling via intercellular
channels organized into gap junctions. Not only do astrocytes establish such homocellular contacts, but they
also engage in intimate heterocellular interactions with neurons, most notably at synaptic sites. As synaptic
structures house the very core of information transfer and processing in the nervous system, astroglial perisyn-
aptic positioning assures that these glial cells can nourish neurons and establish bidirectional communication
with them, functions outlined in the concepts of the astrocytic cradle and multi-partite synapse, respectively.
Astrocytes possess a rich assortment of ligand receptors, ion and water channels, and ion and ligand transport-
ers, which collectively contribute to astrocytic control of homeostasis and excitability. Astroglia control glu-
tamate and adenosine homeostasis to exert modulatory actions aecting the real-time operation of synapses.
Fluctuations of intracellular calcium can lead to the release of various chemical transmitters from astrocytes
through a process termed gliotransmission. Sodium uctuations are closely associated to those of calcium with
both dynamic events interfacing signaling and metabolism. Astrocytes appear fully integrated into the brain
cellular circuitry, being an indispensable part of neural networks.
is volume is a printed version of a work that appears in the Colloquium
Digital Library of Life
Sciences. Colloquium titles cover all of cell and molecular biology and biomedicine, includ-
ing the neurosciences, from the advancedundergraduate and graduate level up to the post-
graduate and practicing researcher level. ey oer concise, original presentations of important
research and development topics, published quickly, in digital
and print formats. For more
information, visit www.morganclaypool.com
Series Editors: Alexei Verkhratsky & Vladimir Parpura Series Editors: Alexei Verkhratsky & Vladimir Parpura
ISSN 2375-9933
Colloquium series on
neuroglia in Biology and mediCine
from physiology to disease
MORGAN & CLAYPOOL LIFE SCIENCES
www.morganclaypool.com
ISBN: 978-1-61504-672-0
9 781615 046720
90000
life sciences
MORGAN & CLAYPOOL LIFE SCIENCES
life sciences
Colloquium series on
neuroglia in Biology and mediCine
from physiology to disease
Physiology of Astroglia
Channels, Receptors, Transporters,
Ion Signaling and Gliotransmission
Alexei Verkhratsky
Vladimir Parpura
Series Editor: Michael Dean, Ph.D.
VERKHRATSKY • PARPURA PH YSIOLOGY OF ASTROGLIA
MORGAN&CLAYPOOL
Physiology of Astroglia
Alexei Verkhratsky, M.D., Ph.D., D.Sc., M.A.E., M.L., M.R.A.N.F.,
e University of Manchester, Manchester, U.K.; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Vladimir Parpura, M.D., Ph.D., M.A.E., Department of Neurobiology, Center for Glial Biology in Medicine,
Atomic Force Microscopy & Nanotechnology Laboratories, Civitan International Research Center,
Evelyn F. McKnight Brain Institute, University of Alabama, Birmingham, AL, U.S.A.;
Department of Biotechnology, University of Rijeka, Croatia
Astrocytes can be dened as the glia inhabiting the nervous system with the main function in the maintenance
of nervous tissue homeostasis. Classied into several types according to their morphological appearance, many
of astrocytes form a reticular structure known as astroglial syncytium, owing to their coupling via intercellular
channels organized into gap junctions. Not only do astrocytes establish such homocellular contacts, but they
also engage in intimate heterocellular interactions with neurons, most notably at synaptic sites. As synaptic
structures house the very core of information transfer and processing in the nervous system, astroglial perisyn-
aptic positioning assures that these glial cells can nourish neurons and establish bidirectional communication
with them, functions outlined in the concepts of the astrocytic cradle and multi-partite synapse, respectively.
Astrocytes possess a rich assortment of ligand receptors, ion and water channels, and ion and ligand transport-
ers, which collectively contribute to astrocytic control of homeostasis and excitability. Astroglia control glu-
tamate and adenosine homeostasis to exert modulatory actions aecting the real-time operation of synapses.
Fluctuations of intracellular calcium can lead to the release of various chemical transmitters from astrocytes
through a process termed gliotransmission. Sodium uctuations are closely associated to those of calcium with
both dynamic events interfacing signaling and metabolism. Astrocytes appear fully integrated into the brain
cellular circuitry, being an indispensable part of neural networks.
is volume is a printed version of a work that appears in the Colloquium
Digital Library of Life
Sciences. Colloquium titles cover all of cell and molecular biology and biomedicine, includ-
ing the neurosciences, from the advancedundergraduate and graduate level up to the post-
graduate and practicing researcher level. ey oer concise, original presentations of important
research and development topics, published quickly, in digital
and print formats. For more
information, visit www.morganclaypool.com
Series Editors: Alexei Verkhratsky & Vladimir Parpura
Series Editors: Alexei Verkhratsky & Vladimir Parpura
ISSN 2375-9933
Colloquium series on
neuroglia in Biology and mediCine
from physiology to disease
MORGAN & CLAYPOOL LIFE SCIENCES
www.morganclaypool.com
ISBN: 978-1-61504-672-0
9 781615 046720
90000
life sciences
MORGAN & CLAYPOOL LIFE SCIENCES
life sciences
Colloquium series on
neuroglia in Biology and mediCine
from physiology to disease
Physiology of Astroglia:
Channels, Receptors,Transporters,
Ion Signaling, and Gliotransmission
ii
Colloquium
Digital Library of Life Sciences
is e-book is an original work commissioned for the Colloquium Digital Library of Life Sciences, a
curated collection of time-saving pedagogical resources for researchers and students who want to
quickly get up to speed in a new area of life science/biomedical research. Each e-book available in
Colloquium is an in-depth overview of a fast-moving or fundamental area of research, authored by
a prominent contributor to the eld. We call these resources ‘Lectures’ because authors are asked
to provide an authoritative, state-of-the-art overview of their area of expertise, in a manner that
is accessible to a broad, diverse audience of scientists (similar to a plenary or keynote lecture at a
symposium/meeting/colloquium). Readers are invited to keep current with advances in various
disciplines, gain insight into elds other than their own, and refresh their understanding of core
concepts in cell & molecular biology.
For the full list of available Lectures, please visit:
www.morganclaypool.com/page/lifesci
All lectures available as PDF. Access is free for readers at institutions that license Colloquium.
Please e-mail info@morganclaypool.com for more information.
iii
Colloquium Series on
Neuroglia in Biology and Medicine:
From Physiology to Disease
Editors
Alexei Verkhratsky, M.D., Ph.D., D.Sc., M.A.E., M.L., M.R.A.N.F.
e University of Manchester, Manchester, U.K.; IKERBASQUE, Basque Foundation for Science, Bilbao,
Spain; Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa, Spain; Uni-
versity of Nizhny Novgorod, Nizhny Novgorod 603022, Russia
Vladimir Parpura, M.D., Ph.D., M.A.E.
Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy & Nan-
otechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain Institute,
University of Alabama at Birmingham, Birmingham, AL, U.S.A.; Department of Biotechnology, Uni-
versity of Rijeka, Croatia
is series of e-books is dedicated to physiology and pathophysiology of neuroglia. It will be
valuable for the researchers and workers in the eld of neurobiology and medicine in general.
Illustrations provided will be suitable for professional presentations and instructional materials
by researchers, physicians, teachers and members of the pharmaceutical industry. As the topic of
neuroglia is generally overlooked in the majority of neuroscience curricula, this series could ll a
need for materials to be used in courses and/or seminars aimed at exploring the role of glia in the
brain in health and disease.
For published titles please see the website, www.morganclaypool.com/toc/ngl/1/1.
iv
Copyright © 2015 by Morgan & Claypool
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in
any form or by any means—electronic, mechanical, photocopy, recording, or any other except for brief quotations
in printed reviews, without the prior permission of the publisher.
Physiology of Astroglia: Channels, Receptors, Transporters, Ion Signaling and Gliotransmission
Alexei Verkhratsky and Vladimir Parpura
www.morganclaypool.com
ISBN: 9781615046720 paper
ISBN: 9781615046737 ebook
DOI: 10.4199/C00123ED1V01Y201501NGL004
A Publication in the
COLLOQUIUM SERIES ON NEUROGLIA IN BIOLOGY AND MEDICINE: FROM PHYSIOLOGY
TO DISEASE
Series Editors: Alexei Verkhratsky, e University of Manchester, U.K.; IKERBASQUE, Basque Foundation
for Science, Bilbao, Spain; Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa,
Spain and Vladimir Parpura, Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force
Microscopy & Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain
Institute, University of Alabama at Birmingham, Birmingham, U.S.A.; Department of Biotechnology, University
of Rijeka, Croatia
Series ISSN
ISSN 2375-9933 print
ISSN 2375-9917 electronic
Physiology of Astroglia:
Channels, Receptors,Transporters,
Ion Signaling , and Gliotransmission
Alexei Verkhratsky1, 2, 3 and Vladimir Parpura4, 5
1 Faculty of Life Sciences, e University of Manchester, Manchester, U.K.
2 Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain;
and Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa, Spain
3 University of Nizhny Novgorod, Nizhny Novgorod 603022, Russia
4 Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy &
Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain
Institute, University of Alabama at Birmingham, Birmingham, AL, U.S.A.
5 Department of Biotechnology, University of Rijeka, Rijeka, Croatia
COLLOQUIUM SERIES ON NEUROGLIA IN BIOLOGY AND MEDICINE:
FROM PHYSIOLOGY TO DISEASE
M
&CMORGAN & CLAYPOOL LIFE SCIENCES
vi
ABSTRACT
Astrocytes can be dened as the glia inhabiting the nervous system with the main function in
the maintenance of nervous tissue homeostasis. Classied into several types according to their
morphological appearance, many of astrocytes form a reticular structure known as astroglial syn-
cytium, owing to their coupling via intercellular channels organized into gap junctions. Not only
do astrocytes establish such homocellular contacts, but they also engage in intimate heterocellular
interactions with neurons, most notably at synaptic sites. As synaptic structures house the very
core of information transfer and processing in the nervous system, astroglial perisynaptic position-
ing assures that these glial cells can nourish neurons and establish bidirectional communication
with them, functions outlined in the concepts of the astrocytic cradle and multi-partite synapse,
respectively. Astrocytes possess a rich assortment of ligand receptors, ion and water channels, and
ion and ligand transporters, which collectively contribute to astrocytic control of homeostasis and
excitability. Astroglia control glutamate and adenosine homeostasis to exert modulatory actions
aecting the real-time operation of synapses. Fluctuations of intracellular calcium can lead to the
release of various chemical transmitters from astrocytes through a process termed gliotransmission.
Sodium uctuations are closely associated to those of calcium with both dynamic events interfacing
signaling and metabolism. Astrocytes appear fully integrated into the brain cellular circuitry, being
an indispensable part of neural networks.
KEY WORDS
astroglia, calcium signaling, homeostasis, ion channels, neurotransmitters, receptors, sodium
signaling, synaptic transmission, transporters
vii
Contents
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
1 Astrocytes: General Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Astroglia: Denition and Identication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Astroglial Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.3 Astroglial Syncytia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.4 Astroglia and Synapse: e Concept of Multi-Partite Synapse and
Astroglial Cradle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.4.1 Multi-Partite Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.4.2 Astroglial Synaptic Coverage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.4.3 Astrocytes Cradle: Fostering and Maintaining Synaptic
Connectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2 Ion Distribution and Membrane Potential . . . . . . . . . . . . . . . . . . . . . . 23
2.1 Ion Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.2 Membrane Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.3 Astrocytes Are Electrically Non-Excitable Cells . . . . . . . . . . . . . . . . . . . . . . 25
3 Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1 Ion Channels: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.2 Potassium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.2.1 Inward Rectier Potassium Channels, Kir . . . . . . . . . . . . . . . . . . . . 29
3.2.2 Voltage-Independent K+ Channels . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.2.3 Voltage-Gated K+ Channels, Kv . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.2.4 Ca2+-Dependent K+ Channels, KCa . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.2.5 A Note on Astroglia as Central Element of Extracellular
Potassium Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.3 Sodium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.3.1 Voltage-Gated Sodium Channels, Nav . . . . . . . . . . . . . . . . . . . . . . 34
3.3.2 [Na+]o-Regulated Na+ Channels, Nax . . . . . . . . . . . . . . . . . . . . . . . . 35
3.4 Calcium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
viii
3.4.1 Voltage-Gated Ca2+ Channels . . . . . . . . . . . . . . . . . . . . . . . . 37
3.4.2 Store-Operated Ca2+ Channels of Orai Family . . . . . . . . . . . 37
3.5 Intracellular Ca2+ Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.6 Transient Receptor Potential (TRP Channels) . . . . . . . . . . . . . . . . . . 39
3.6.1 TRPC Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.6.2 TRPA1 Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.6.3 TRPV Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.7 Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN)
Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.8 Anion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.9 Aquaporins or Water Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.9.1 A Note on Water Homeostasis, Extracellular space, and
Glymphatic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.10 Connexons and Connexins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.11 Pannexons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4 Neurotransmitter Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.1 Receptors for Neurotransmitters and Neurohormones:
An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.2 Astroglia Express Multiple Receptors . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.3 Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.3.1 Ionotropic Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . 55
4.3.2 Metabotropic Glutamate Receptors . . . . . . . . . . . . . . . . . . . . 58
4.4 Purinoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
4.4.1 Adenosine (P1) Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.4.2 P2Y Metabotropic Purinoceptors . . . . . . . . . . . . . . . . . . . . . 60
4.4.3 Ionotropic P2X Purinoceptors . . . . . . . . . . . . . . . . . . . . . . . . 60
4.5 Receptors for Inhibitory Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . 61
4.5.1 GABA Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
4.5.2 Glycine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.6 Other Types of Receptors for Neurotransmitters and
Neuromodulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.6.1 Acetylcholine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.6.2 Adrenergic Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
4.6.3 Serotonin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
4.6.4 Histamine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.6.5 Bradykinin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
ix
4.6.6 Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.6.7 Neuropeptide Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.6.8 Leptin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.6.9 Cytokine and Chemokine Receptors . . . . . . . . . . . . . . . . . . . . . . . . 65
4.6.10 Complement Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4.6.11 Platelet-Activating Factor Receptor . . . . . . . . . . . . . . . . . . . . . . . . 66
4.6.12 rombin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4.6.13 Ephrin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.6.14 Succinate Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.6.15 Toll-Like Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.6.16 PACAP Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.6.17 Astroglia and Glucose Sensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
5 Membrane Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
5.1 An Overview of Membrane Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
5.2 ATP-Dependent Transporters in Astroglia . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5.2.1 Astroglial P-Type Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5.2.2 Astroglial F- and V-Type Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
5.2.3 Astroglial ABC-Binding Cassette Transporters . . . . . . . . . . . . . . . . 73
5.3 Secondary Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
5.3.1 Plasmalemmal Glutamate Transporters . . . . . . . . . . . . . . . . . . . . . . 73
5.3.2 Sxc- Cystine/Glutamate Antiporter . . . . . . . . . . . . . . . . . . . . . . . . . 74
5.3.3 Glutamine Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
5.3.4 GABA Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
5.3.5 Glycine Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
5.3.6 Adenosine Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
5.3.7 Dopamine Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.3.8 D-serine Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
5.3.9 A Note on Astroglial Role in Regulation of Neurotransmitters
Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
5.3.10 Plasmalemmal Sodium-Calcium Exchanger (NCX) . . . . . . . . . . . . 86
5.3.11 Sodium-Proton Exchanger (NHE) . . . . . . . . . . . . . . . . . . . . . . . . . 87
5.3.12 Sodium-Bicarbonate Co-Transporter (NBC) . . . . . . . . . . . . . . . . . 88
5.3.13 A Note on Astrocytes and Regulation of pH in the CNS . . . . . . . . 89
5.3.14 A Note on Astroglia and Central Chemoception of pH and CO2 . . 89
5.3.15 Sodium-Potassium-Chloride Co-Transporter (NKCC1) . . . . . . . . 91
5.3.16 Vesicular Neurotransmitter Transporters . . . . . . . . . . . . . . . . . . . . . 91
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5.3.17 Monocarboxylate Transporters (MCTs) . . . . . . . . . . . . . . . . . . . . . 91
5.3.18 Ascorbic Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
5.3.19 A Note on the Astroglial Antioxidant System . . . . . . . . . . . . . . . . . 92
5.3.20 Zinc Transporter and Zinc Homeostasis . . . . . . . . . . . . . . . . . . . . . 94
6 Ionic Signaling in Astroglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
6.1 Calcium Signaling: General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
6.1.1 Calcium Signaling: An Evolutionary Perspective . . . . . . . . . . . . . . . 95
6.1.2 Calcium Signaling: Molecular Mechanisms . . . . . . . . . . . . . . . . . . . 96
6.2 Calcium Signaling and Astroglial Excitability . . . . . . . . . . . . . . . . . . . . . . 101
6.2.1 Endoplasmic Reticulum Provides for Ca2+ Excitability of
Astrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
6.2.2 Store-Operated Ca2+ Entry in Astrocytes . . . . . . . . . . . . . . . . . . . 103
6.2.3 Ionotropic Ca2+ Permeable Receptors in Astrocytes . . . . . . . . . . . . 103
6.2.4 Plasmalemmal Sodium/Calcium Exchanger in Astroglial Ca2+
Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
6.2.5 Mitochondria in Astroglial Ca2+ Signaling . . . . . . . . . . . . . . . . . . . 105
6.2.6 Calcium Waves in Astrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
6.3 Sodium Signaling in Astrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
7 Gliotransmission: Astrocytes as Secretory Cells of the Nervous System . . . . 113
7.1 e Fundamentals of Chemical Neurotransmission . . . . . . . . . . . . . . . . . . 113
7.2 e Concept of Astroglia as Secretory Cells in the CNS . . . . . . . . . . . . . . 114
7.3 Astrocytes Secrete Multiple Neuroactive Substances . . . . . . . . . . . . . . . . . . 117
7.4 Astroglial Secretion Proceeds by Multiple Molecular Pathways . . . . . . . . . 119
7.4.1 Exocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
7.4.2 Diusional Release of Neurotransmitters from Astrocytes. . . . . . . 122
7.4.3 Transporter-Mediated Neurotransmitter Release from
Astrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
7.5 Main Neurotransmitters and Neuromodulators Released from
Astrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
7.5.1 Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
7.5.2 ATP/Adenosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
7.5.3 GABA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
7.5.4 D-Serine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
7.5.5 Kynurenic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
7.5.6 Lactate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
7.5.7 Glutamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
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Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Author Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
... Today, we know that astrocytes comprise a morphologically and functionally highly heterogeneous class of cells, which makes their identification difficult (Griemsmann et al., 2015;Matyash & Kettenmann, 2010;. Common characteristics include the absence of electrical excitability, a high resting K + conductance and therefore a membrane potential close to the K + equilibrium potential, extensive connections to each other via gap junctions, expression of functional glutamate and GABA transporters, formation of numerous fine processes enwrapping synapses and blood vessels, and expression of intermediate filament proteins such as GFAP and vimentin (Verkhratsky & Parpura, 2015). Research over the past decades revealed that astrocytes are way more than "nerve glue" as they fulfill a plethora of vital physiological functions and, consequently, are also key players in neurological diseases (Parpura et al., 2012;Seifert, Schilling, & Steinhäuser, 2006;Verkhratsky & Parpura, 2015). ...
... Common characteristics include the absence of electrical excitability, a high resting K + conductance and therefore a membrane potential close to the K + equilibrium potential, extensive connections to each other via gap junctions, expression of functional glutamate and GABA transporters, formation of numerous fine processes enwrapping synapses and blood vessels, and expression of intermediate filament proteins such as GFAP and vimentin (Verkhratsky & Parpura, 2015). Research over the past decades revealed that astrocytes are way more than "nerve glue" as they fulfill a plethora of vital physiological functions and, consequently, are also key players in neurological diseases (Parpura et al., 2012;Seifert, Schilling, & Steinhäuser, 2006;Verkhratsky & Parpura, 2015). Their functions include supply of nutrients to neurons, control of extracellular ion homeostasis, clearance of neurotransmitters, regulation of the bloodbrain barrier (BBB) permeability, promotion of synapse formation, and contribution to the immune response by release of proinflammatory cytokines or neurotrophic factors (Verkhratsky & Parpura, 2015). ...
... Research over the past decades revealed that astrocytes are way more than "nerve glue" as they fulfill a plethora of vital physiological functions and, consequently, are also key players in neurological diseases (Parpura et al., 2012;Seifert, Schilling, & Steinhäuser, 2006;Verkhratsky & Parpura, 2015). Their functions include supply of nutrients to neurons, control of extracellular ion homeostasis, clearance of neurotransmitters, regulation of the bloodbrain barrier (BBB) permeability, promotion of synapse formation, and contribution to the immune response by release of proinflammatory cytokines or neurotrophic factors (Verkhratsky & Parpura, 2015). Importantly, astrocytes also directly modulate synaptic transmission by release, uptake, degradation, and recycling of transmitters (Araque et al., 2014;Verkhratsky & Nedergaard, 2018). ...
Properties of human astrocytes and NG2 glia
Article
Full-text available
Since animal models are inevitable for medical research, information on species differences in glial cell properties is critical for successful translational research. Here, we review current knowledge about morphological and functional properties of human astrocytes and NG2 glial cells and compare these data with those obtained for the comparable cells in rodents. Morphological analyses of astrocytes in the neocortex of rodents versus humans have demonstrated clear differences. In contrast, the functional properties of astrocytes or NG2 glial cells in these species are surprisingly similar. However, these findings should be interpreted with caution, as so far functional analyses of human cells are only available from neocortex and hippocampus, and it is known from rodent studies that the properties of astrocytes in different brain regions may vary considerably. Moreover, technical challenges render astrocyte electrophysiological measurements in situ unreliable, and human cell properties may be affected by medications. Nevertheless, based on the limited data currently available, there is substantial similarity between human and rodent astrocytes with regard to those functional properties studied to date. The unique morphological characteristics of astrocytes in human neocortex call for further physiological analysis. The basic properties for NG2 glia are even less completely evaluated with regard to the question of species differences but no glaring differences have been reported so far. In conclusion, it remains justifiable to employ mouse or rat models to investigate the etiology of human CNS diseases that might involve astrocytes or NG2 glia.
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... NKA, sodiumpotassium ATPase. Modified from [413] Astroglial TRP channels. Activation of G-protein coupled receptors (GPCR), i.e. metabotropic stimulation, can lead to production of InsP 3 and release of Ca 2+ from the ER store. ...
... Activation of all TRP channels mediates Ca 2+ and Na + influx. Modified from [413] Classes of purinoreceptors. ATP after being released from neurones and glia is rapidly degrading by ectonucleotidases into ADP, AMP and adenosine, which act on P1 metabotropic adenosine receptors, P2X ionotropic and P2Y metabotropic nucleotide receptors. ...
... Reactive oxygen species (ROS). Modified from [413] ...
Physiology of Astroglia
Chapter
  • Oct 2019
  • ADV EXP MED BIOL
Astrocytes are principal cells responsible for maintaining the brain homeostasis. Additionally, these glial cells are also involved in homocellular (astrocyte-astrocyte) and heterocellular (astrocyte-other cell types) signalling and metabolism. These astroglial functions require an expression of the assortment of molecules, be that transporters or pumps, to maintain ion concentration gradients across the plasmalemma and the membrane of the endoplasmic reticulum. Astrocytes sense and balance their neurochemical environment via variety of transmitter receptors and transporters. As they are electrically non-excitable, astrocytes display intracellular calcium and sodium fluctuations, which are not only used for operative signalling but can also affect metabolism. In this chapter we discuss the molecules that achieve ionic gradients and underlie astrocyte signalling.
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... Rights reserved. by astroglial activity (Verkhratsky and Parpura 2015). Astrogliogenesis begins very early in the fetal primate cortex (Kostović et al 2019a;Schmechel and Rakic 1979), and astrocytes can release various chemical transmitters, i.e., "gliotransmission", and participate in bidirectional signaling with neurons (Verkhratsky and Parpura 2015). ...
... by astroglial activity (Verkhratsky and Parpura 2015). Astrogliogenesis begins very early in the fetal primate cortex (Kostović et al 2019a;Schmechel and Rakic 1979), and astrocytes can release various chemical transmitters, i.e., "gliotransmission", and participate in bidirectional signaling with neurons (Verkhratsky and Parpura 2015). Our results on early synaptogenesis in the human fetal cortex can explain, to some extent, the early appearance of lamina-characteristic types of astroglia as prospective players in synapse formation of the human fetal cortex (Kostović et al. 2019a). ...
Development of the basic architecture of neocortical circuitry in the human fetus as revealed by the coupling spatiotemporal pattern of synaptogenesis along with microstructure and macroscale in vivo MR imaging
Article
Full-text available
  • Aug 2024
  • BRAIN STRUCT FUNCT
In humans, a quantifiable number of cortical synapses appears early in fetal life. In this paper, we present a bridge across different scales of resolution and the distribution of synapses across the transient cytoarchitectonic compartments: marginal zone (MZ), cortical plate (CP), subplate (SP), and in vivo MR images. The tissue of somatosensory cortex (7–26 postconceptional weeks (PCW)) was prepared for electron microscopy, and classified synapses with a determined subpial depth were used for creating histograms matched to the histological sections immunoreacted for synaptic markers and aligned to in vivo MR images (1.5 T) of corresponding fetal ages (maternal indication). Two time periods and laminar patterns of synaptogenesis were identified: an early and midfetal two-compartmental distribution (MZ and SP) and a late fetal three-compartmental distribution (CP synaptogenesis). During both periods, a voluminous, synapse-rich SP was visualized on the in vivo MR. Another novel finding concerns the phase of secondary expansion of the SP (13 PCW), where a quantifiable number of synapses appears in the upper SP. This lamina shows a T2 intermediate signal intensity below the low signal CP. In conclusion, the early fetal appearance of synapses shows early differentiation of putative genetic mechanisms underlying the synthesis, transport and assembly of synaptic proteins. “Pioneering” synapses are likely to play a morphogenetic role in constructing of fundamental circuitry architecture due to interaction between neurons. They underlie spontaneous, evoked, and resting state activity prior to ex utero experience. Synapses can also mediate genetic and environmental triggers, adversely altering the development of cortical circuitry and leading to neurodevelopmental disorders.
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... regulating ion and neurotransmitter concentrations in the CNS), metabolic homeostasis (e.g. producing lactate that they can provide neurons), and heterocellular signaling Verkhratsky, 2012b, 2012c;Verkhratsky and Parpura, 2015). ...
... Upon internalizing neurotransmitters, astrocytes catabolize them. For example, they can use glutamine synthetase to convert glutamate to glutamine, which is then supplied to neurons as the obligate precursor for glutamate and GABA synthesis (Verkhratsky and Parpura, 2015). Astrocytes also catabolize adenosine by phosphorylating it using adenosine kinase. ...
Neural Stem Cells in Adult Mammals are not Astrocytes
Article
Full-text available
  • Nov 2022
At the turn of the 21st century studies of the cells that resided in the adult mammalian subventricular zone (SVZ) characterized the neural stem cells (NSCs) as a subtype of astrocyte. Over the ensuing years, numerous studies have further characterized the properties of these NSCs and compared them to parenchymal astrocytes. Here we have evaluated the evidence collected to date to establish whether classifying the NSCs as astrocytes is appropriate and useful. We also performed a meta-analysis with 4 previously published datasets that used cell sorting and unbiased single-cell RNAseq to highlight the distinct gene expression profiles of adult murine NSCs and niche astrocytes. On the basis of our understanding of the properties and functions of astrocytes versus the properties and functions of NSCs, and from our comparative transcriptomic analyses we conclude that classifying the adult mammalian NSC as an astrocyte is potentially misleading. From our vantage point, it is more appropriate to refer to the cells in the adult mammalian SVZ that retain the capacity to produce new neurons and macroglia as NSCs without attaching the term “astrocyte-like.”
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... In this way, they finely regulate synaptic transmission by tuning neurotransmitter levels in the synaptic cleft . Astrocytes are fundamental components of the BBB where their presence is essential for a protective function and the control of cerebral flow, thus regulating the communication between the CNS and the periphery (Verkhratsky and Parpura 2015). Astrocytes are also a part of the so-called gliocrine system, releasing around 200 molecules, mainly neurotrophic factors, and energy substrates, fundamental for the maintenance of CNS functions ). ...
Neuroglia in Psychiatric Disorders
Chapter
  • Dec 2021
In the twentieth century, neuropsychiatric disorders have been perceived solely from a neurone-centric point of view, which considers neurones as the key cellular elements of pathological processes. This dogma has been challenged thanks to the better comprehension of the brain functioning, which, even if far from being complete, has revealed the complexity of interactions that exist between neurones and neuroglia. Glial cells represent a highly heterogeneous population of cells of neural (astroglia and oligodendroglia) and non-neural (microglia) origin populating the central nervous system. The variety of glia reflects the innumerable functions that glial cells perform to support functions of the nervous system. Aberrant execution of glial functions contributes to the development of neuropsychiatric pathologies. Arguably, all types of glial cells are implicated in the neuropathology; however, astrocytes have received particular attention in recent years because of their pleiotropic functions that make them decisive in maintaining cerebral homeostasis. This chapter describes the multiple roles of astrocytes in the healthy central nervous system and discusses the diversity of astroglial responses in neuropsychiatric disorders suggesting that targeting astrocytes may represent an effective therapeutic strategy.
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... Astrocytes are homeostatic cells of the central nervous system (CNS). They control multiple aspects of brain physiology at all levels of organization from molecular to organ and systemic (Verkhratsky and Butt 2013;Verkhratsky and Parpura 2015;Verkhratsky and Nedergaard 2018). An individual protoplasmic astrocyte interacts with as many as 100,000 synapses in mice and possibly up to 2,000,000 synapses in humans (Bushong et al. 2002;Oberheim et al. 2009); these astrocytic perisynaptic structures, known as synaptic cradle (Verkhratsky and Nedergaard 2014), are fundamental for maintaining neurotransmission in the CNS. ...
Astroglial Serotonin Receptors as the Central Target of Classic Antidepressants
Chapter
  • Dec 2021
Major depressive disorder (MDD) presents multiple clinical phenotypes and has complex underlying pathological mechanisms. Existing theories cannot completely explain the pathophysiological mechanism(s) of MDD, while the pharmacology of current antidepressants is far from being fully understood. Astrocytes, the homeostatic and defensive cells of the central nervous system, contribute to shaping behaviors, and regulating mood and emotions. A detailed introduction on the role of astrocytes in depressive disorders is thus required, to which this chapter is dedicated. We also focus on the interactions between classic antidepressants and serotonin receptors, overview the role of astrocytes in the pharmacological mechanisms of various antidepressants, and present astrocytes as targets for the treatment of bipolar disorder. We provide a foundation of knowledge on the role of astrocytes in depressive disorders and astroglial 5-HT2B receptors as targets for selective serotonin reuptake inhibitors in vivo and in vitro.
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... Another organelle, the mitochondrion, participates in buffering cytosolic Ca 2+ transients, which drive vesicular glutamate release [27]. At high cytosolic levels, mitochondrial Ca 2+ uptake is mediated by the Ca 2+ uniporter complex, containing voltage-dependent anion-selective channel protein (VDAC), that has considerable Ca 2+ permeability, on the outer mitochondrial membrane and the highly selective mitochondrial Ca 2+ uniporter complex (composed of mitochondrial Ca 2+ uniporter MCU1/2, mitochondrial EF hand Ca 2+ uniporter regulator MICU1/2, essential MCU regulator EMRE, and mitochondrial Ca 2+ uniporter regulator MCUR1) on the inner membrane; see reviewed in [99]. While we detected VDAC 1, 2 and 3 at similar levels in all preparations, respectively, we have not detected any of the inner membrane components of this complex. ...
Two Metabolic Fuels, Glucose and Lactate, Differentially Modulate Exocytotic Glutamate Release from Cultured Astrocytes
Article
Full-text available
  • Oct 2021
  • NEUROCHEM RES
Astrocytes have a prominent role in metabolic homeostasis of the brain and can signal to adjacent neurons by releasing glutamate via a process of regulated exocytosis. Astrocytes synthesize glutamate de novo owing to the pyruvate entry to the citric/tricarboxylic acid cycle via pyruvate carboxylase, an astrocyte specific enzyme. Pyruvate can be sourced from two metabolic fuels, glucose and lactate. Thus, we investigated the role of these energy/carbon sources in exocytotic glutamate release from astrocytes. Purified astrocyte cultures were acutely incubated (1 h) in glucose and/or lactate-containing media. Astrocytes were mechanically stimulated, a procedure known to increase intracellular Ca2+ levels and cause exocytotic glutamate release, the dynamics of which were monitored using single cell fluorescence microscopy. Our data indicate that glucose, either taken-up from the extracellular space or mobilized from the intracellular glycogen storage, sustained glutamate release, while the availability of lactate significantly reduced the release of glutamate from astrocytes. Based on further pharmacological manipulation during imaging along with tandem mass spectrometry (proteomics) analysis, lactate alone, but not in the hybrid fuel, caused metabolic changes consistent with an increased synthesis of fatty acids. Proteomics analysis further unveiled complex changes in protein profiles, which were condition-dependent and generally included changes in levels of cytoskeletal proteins, proteins of secretory organelle/vesicle traffic and recycling at the plasma membrane in aglycemic, lactate or hybrid-fueled astrocytes. These findings support the notion that the availability of energy sources and metabolic milieu play a significant role in gliotransmission.
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... One of the most commonly used astrocyte markers is the intermediate filament protein glial fibrillary acidic protein (GFAP) [18,19]. However, GFAP labels only a subset of astrocytes and not all cells in the brain that express GFAP are astrocytes [20]. ...
Role of Astrocytes in Major Neuropsychiatric Disorders
Article
Full-text available
  • Jan 2021
  • NEUROCHEM RES
Astrocytes are the primary homeostatic cells of the central nervous system, essential for normal neuronal development and function, metabolism and response to injury and inflammation. Here, we review postmortem studies examining changes in astrocytes in subjects diagnosed with the neuropsychiatric disorders schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BPD). We discuss the astrocyte-related changes described in the brain in these disorders and the potential effects of psychotropic medication on these findings. Finally, we describe emerging tools that can be used to study the role of astrocytes in neuropsychiatric illness.
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... Astrocytes are primary homeostatic cells of the central nervous system (CNS), which control multiple aspects of brain physiology at all levels of organization from molecular to organ and systemic [1,2]. Pathological changes in astroglial cells, represented by astrogliosis, or astrodegeneration or atrophy with loss of function are salient features of all neurological disorders [3,4] including neurodevelopmental [5] and neuropsychiatric [6][7][8] diseases. ...
Astroglial 5-HT 2B receptor in mood disorders
Article
  • Mar 2018
Introduction: Astroglia represent the main cellular homeostatic system of the central nervous system (CNS). Astrocytes are intimately involved in regulation and maintenance of neurotransmission by regulating neurotransmitters removal and turnover and by supplying neurons with neurotransmitters precursors. Astroglial cells are fundamental elements of monoaminergic transmission in the brain and in the spinal cord. Astrocytes receive monoaminergic inputs and control catabolism of monoamines through dedicated transporters and intracellular enzymatic pathways. Areas covered: Astroglial cells express serotonergic receptors; in this review, we provide an in-depth characterization of 5-HT2B receptors. Activation of these receptors triggers numerous intracellular signaling cascades that regulate expression of multiple genes. Astroglial 5-HT2B receptors are activated by serotonin-specific reuptake inhibitors, such as major anti-depressant fluoxetine. Expression of astroglial serotonin receptors undergoes remarkable changes in depression disorders, and these changes can be corrected by chronic treatment with anti-depressant drugs. Expert commentary: Depressive behaviors, which occur in rodents following chronic stress or in neurotoxic models of Parkinson disease, are associated with significant changes in the expression of astroglial, but not neuronal 5-HT2B receptors; while therapy with anti-depressants normalizes both receptors expression and depressive behavioral phenotype. In summary, astroglial serotonin receptors are linked to mood disorders and may represent a novel target for cell- and molecule-specific therapies of depression and mood disorders.
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... However, this neurocentric view of epilepsy has recently been challenged by a number of studies demonstrating a crucial role of glial cells in influencing neuronal activity, brain homeostasis and neuroprotection. Astrocytes, the most abundant glial population, fulfill various important functions in the brain including direct modulation of synaptic transmission by release, uptake, degradation and recycling of transmitters, control of the extracellular ion and water homeostasis, regulation of local blood flow, maintenance of BBB integrity, and supply of nutrients to neurons (Verkhratsky & Parpura, 2015). Importantly, astrocytes are electrically and metabolically connected to each other by gap junctions composed mainly of Cx43 and Cx30 to form functional networks (Giaume, Koulakoff, Roux, Holcman, & Rouach, 2010;Nagy & Rash, 2000). ...
Subcellular reorganization and altered phosphorylation of the astrocytic gap junction protein connexin43 in human and experimental temporal lobe epilepsy
Article
Full-text available
  • Aug 2017
Dysfunctional astrocytes are increasingly recognized as key players in the development and progression of mesial temporal lobe epilepsy (MTLE). One of the dramatic changes astrocytes undergo in MTLE with hippocampal sclerosis (HS) is loss of gap junction coupling. To further elucidate molecular mechanism(s) underlying this alteration, we assessed expression, cellular localization and phosphorylation status of astrocytic gap junction proteins in human and experimental MTLE-HS. In addition to conventional confocal analysis of immunohistochemical staining we employed expansion microscopy, which allowed visualization of blood-brain-barrier (BBB) associated cellular elements at a sub-µm scale. Western Blot analysis showed that plasma membrane expression of connexin43 (Cx43) and Cx30 were not significantly different in hippocampal specimens with and without sclerosis. However, we observed a pronounced subcellular redistribution of Cx43 toward perivascular endfeet in HS, an effect that was accompanied by increased plaque size. Furthermore, in HS Cx43 was characterized by enhanced C-terminal phosphorylation of sites affecting channel permeability. Prominent albumin immunoreactivity was found in the perivascular space of HS tissue, indicating that BBB damage and consequential albumin extravasation was involved in Cx43 dysregulation. Together, our results suggest that subcellular reorganization and/or abnormal posttranslational processing rather than transcriptional downregulation of astrocytic gap junction proteins account for the loss of coupling reported in human and experimental TLE. The observations of the present study provide new insights into pathological alterations of astrocytes in HS, which may aid in the identification of novel therapeutic targets and development of alternative anti-epileptogenic strategies.
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Protoplasmic Astrocytes in CA1 Stratum Radiatum Occupy Separate Anatomical Domains
Article
Full-text available
  • Jan 2002
Protoplasmic astrocytes are increasingly thought to interact extensively with neuronal elements in the brain and to influence their activity. Recent reports have also begun to suggest that physiologically, and perhaps functionally, diverse forms of these cells may be present in the CNS. Our current understanding of astrocyte form and distribution is based predominately on studies that used the astrocytic marker glial fibrillary acidic protein (GFAP) and on studies using metal-impregnation techniques. The prevalent opinion, based on studies using these methods, is that astrocytic processes overlap extensively and primarily share the underlying neuropil. However, both of these techniques have serious shortcomings for visualizing the interactions among these structurally complex cells. In the present study, intracellular injection combined with immunohistochemistry for GFAP show that GFAP delineates only ∼15% of the total volume of the astrocyte. As a result, GFAP-based images have led to incorrect conclusions regarding the interaction of processes of neighboring astrocytes. To investigate these interactions in detail, groups of adjacent protoplasmic astrocytes in the CA1 stratum radiatum were injected with fluorescent intracellular tracers of distinctive emissive wavelengths and analyzed using three-dimensional (3D) confocal analysis and electron microscopy. Our findings show that protoplasmic astrocytes establish primarily exclusive territories. The knowledge of how the complex morphology of protoplasmic astrocytes affects their 3D relationships with other astrocytes, oligodendroglia, neurons, and vasculature of the brain should have important implications for our understanding of nervous system function.
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Calcium in the Early Evolution of Living Systems: A Biohistorical Approach
Article
Full-text available
  • Jul 2013
  • CURR ORG CHEM
The possible role of Ca2+ as a promoter of the major steps in the evolution of early life is reviewed. The existing biological knowledge about the role of calcium in living systems is summarized and compared with the major bio-evolutionary events that occurred during the first three billion years of Earth's history. It is proposed that secular changes in Ca2+ concentration in the marine realm during the Precambrian were the crucial driving force behind major innovations in the evolution of early life, such as photosynthesis, eukaryogenesis, multicellularity, origin of metazoans, biocalcification and skeletogenesis.
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LEISHMANIASIS: PRUEBAS MOLECULARES APLICADAS AL DIAGNÓSTICO E IDENTIFICACIÓN DE ESPECIES DE Leishmania sp. EN UNA ZONA ENDÉMICA DEL ESTADO COJEDES
Conference Paper
Full-text available
Distribución de las formas clínicas de la LTA en la República Bolivariana de Venezuela y pruebas disponibles en dispensarios y consultas de parasitología para el diagnóstico de la Leishmaniasis. LCL: Leishmaniasis cutánea localizada; LCM: leishmaniasis cutánea mucosa; LCD: leishmaniasis cutánea difusa.
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Parallel Jacobi EVD Methods on Integrated Circuits
Article
Full-text available
  • Jul 2014
  • VLSI Des
Design strategies for parallel iterative algorithms are presented. In order to further study different tradeoff strategies in design criteria for integrated circuits, A 10 × 10 Jacobi Brent-Luk-EVD array with the simplified μ -CORDIC processor is used as an example. The experimental results show that using the μ -CORDIC processor is beneficial for the design criteria as it yields a smaller area, faster overall computation time, and less energy consumption than the regular CORDIC processor. It is worth to notice that the proposed parallel EVD method can be applied to real-time and low-power array signal processing algorithms performing beamforming or DOA estimation.
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The evolution of the biochemistry of calcium
Article
  • Jan 2007
  • New Compr Biochem
The chemistry of the calcium (Ca) ion does not appear of great interest, but it has been an essential element in biological evolution. Initially, procaryotic cells treated it as an intracellular poison rejecting it together with sodium and chloride ions. The resulting functions of Ca apart from being pumped out of cells were on the cell exterior, assisting such activities as wall stability and extra-cytoplasmic digestion. These functions have continued in a modified form to this day. The great significance of Ca arose with the very beginnings of eucaryote multi-compartment cells. Here communication between compartments is essential, and additionally a great advantage to cell survival, now of longer life, arose from knowledge of the extracellular environment. Here the large adventitious outside cytoplasmic Ca gradient provided an immediate solution for message transmission. It was further aided by ion storage in many internal vesicles. The development needed new channel and response proteins. As multi-compartment eucaryotes evolved further to multicellular organisms and then animals with brains, a succession of functions for Ca signals developed coupled to new organic messengers so that Ca became essential to the whole homeostatic integration of organisms and their activities. There is an inevitability about this progression seen in the multiplicity of old and new Ca proteins. Slowly too the complexity of Ca minerals in shells and bones arose. The latest place in the evolution of the functional value of Ca is mankind's application of it, outside biological evolution, in materials science, cements and plasters for example.
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Neuron-Glia Interactions in Homeostasis and Degeneration
Article
  • Jan 1996
The term “glia” was coined in the middle of the last century by the German pathologist Virchow to designate a class of cells surrounding neurons of the central nervous system (CNS), supposedly serving the nervous system as a kind of “glue” (the meaning of the Greek word glia). Since then it has become clear that glial cells outnumber the neurons of the CNS by at least one order of magnitude. Yet, because glial cells do not convey electrical excitation they have not attracted as much attention as their prominent neighbors in the nervous system and have at best been ascribed merely auxiliary functions. It is only during the past two decades that progress in cell biology has provided insights into the various facets of glial cell functions, and it is becoming increasingly clear that glial cells are not only by-standers but actually play an important role in the formation, maintenance, and plasticity of the nervous system. In particular, CNS pathology and regeneration seem to involve glial cell populations in many cases. The present chapter discusses physiologically relevant roles of glial cells in this context.
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Effects of sodium glutamate on the nervous system
Article
  • Jan 1954
  • Keio J Med
1) High concentration of sodium glutamate (as well as sodium aspartate) which is applied into grey matters of motor cortex in dogs, monkeys and men, generates clonic convulsions with very short latent periods.2) Small dose of sodium glutamate which is introduced into circulation in dogs improves the differentiation of conditioned salivary reflexes during 20 minutes after its administration, and continues its action for some hours.3) The above two aspects of the effect of sodium glutamate must be attributable to the direct physiological action of the chemicals on the central nervoos system in higher animals.
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