Review and hypothesis: a potential common link between glial cells, calcium changes, modulation of synaptic transmission, spreading depression, migraine, and epilepsy—H+
Review and hypothesis: a potential common link between glial cells, calcium changes, modulation of synaptic transmission, spreading depression, migraine, and epilepsy—H+
There is significant evidence to support the notion that glial cells can modulate the strength of synaptic connections between nerve cells, and it has further been suggested that alterations in intracellular calcium are likely to play a key role in this process. However, the molecular mechanism(s) by which glial cells modulate neuronal signaling remains contentiously debated. Recent experiments have suggested that alterations in extracellular H+ efflux initiated by extracellular ATP may play a key role in the modulation of synaptic strength by radial glial cells in the retina and astrocytes throughout the brain. ATP-elicited alterations in H+ flux from radial glial cells were first detected from Müller cells enzymatically dissociated from the retina of tiger salamander using self-referencing H+-selective microelectrodes. The ATP-elicited alteration in H+ efflux was further found to be highly evolutionarily conserved, extending to Müller cells isolated from species as diverse as lamprey, skate, rat, mouse, monkey and human. More recently, self-referencing H+-selective electrodes have been used to detect ATP-elicited alterations in H+ efflux around individual mammalian astrocytes from the cortex and hippocampus. Tied to increases in intracellular calcium, these ATP-induced extracellular acidifications are well-positioned to be key mediators of synaptic modulation. In this article, we examine the evidence supporting H+ as a key modulator of neurotransmission, review data showing that extracellular ATP elicits an increase in H+ efflux from glial cells, and describe the potential signal transduction pathways involved in glial cell—mediated H+ efflux. We then examine the potential role that extracellular H+ released by glia might play in regulating synaptic transmission within the vertebrate retina, and then expand the focus to discuss potential roles in spreading depression, migraine, epilepsy, and alterations in brain rhythms, and suggest that alterations in extracellular H+ may be a unifying feature linking these disparate phenomena.
ATP, H, Müller cell, epilepsy, glia, migraine, pH, spreading depression
Malchow, Robert P.
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Tchernookova, Boriana K.
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Choi, Ji-in V
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Smith, Peter J.S.
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Kramer, Richard H.
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Kreitzer, Matthew A.
5807387c-ed8f-4f5d-8008-2fa3ed91a6cf
3 September 2021
Malchow, Robert P.
797922a0-7cea-4d5a-9276-535c0003745e
Tchernookova, Boriana K.
0cc915bc-5ef9-4b5a-8a51-88c876129f3c
Choi, Ji-in V
de747c50-c7c9-4967-a1b2-23912756af0a
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Kramer, Richard H.
2a38de45-b7a8-41f9-a6bd-30bbff0557ce
Kreitzer, Matthew A.
5807387c-ed8f-4f5d-8008-2fa3ed91a6cf
Malchow, Robert P., Tchernookova, Boriana K., Choi, Ji-in V, Smith, Peter J.S., Kramer, Richard H. and Kreitzer, Matthew A.
(2021)
Review and hypothesis: a potential common link between glial cells, calcium changes, modulation of synaptic transmission, spreading depression, migraine, and epilepsy—H+.
Frontiers in Cellular Neuroscience, 15, [693095].
(doi:10.3389/fncel.2021.693095).
Abstract
There is significant evidence to support the notion that glial cells can modulate the strength of synaptic connections between nerve cells, and it has further been suggested that alterations in intracellular calcium are likely to play a key role in this process. However, the molecular mechanism(s) by which glial cells modulate neuronal signaling remains contentiously debated. Recent experiments have suggested that alterations in extracellular H+ efflux initiated by extracellular ATP may play a key role in the modulation of synaptic strength by radial glial cells in the retina and astrocytes throughout the brain. ATP-elicited alterations in H+ flux from radial glial cells were first detected from Müller cells enzymatically dissociated from the retina of tiger salamander using self-referencing H+-selective microelectrodes. The ATP-elicited alteration in H+ efflux was further found to be highly evolutionarily conserved, extending to Müller cells isolated from species as diverse as lamprey, skate, rat, mouse, monkey and human. More recently, self-referencing H+-selective electrodes have been used to detect ATP-elicited alterations in H+ efflux around individual mammalian astrocytes from the cortex and hippocampus. Tied to increases in intracellular calcium, these ATP-induced extracellular acidifications are well-positioned to be key mediators of synaptic modulation. In this article, we examine the evidence supporting H+ as a key modulator of neurotransmission, review data showing that extracellular ATP elicits an increase in H+ efflux from glial cells, and describe the potential signal transduction pathways involved in glial cell—mediated H+ efflux. We then examine the potential role that extracellular H+ released by glia might play in regulating synaptic transmission within the vertebrate retina, and then expand the focus to discuss potential roles in spreading depression, migraine, epilepsy, and alterations in brain rhythms, and suggest that alterations in extracellular H+ may be a unifying feature linking these disparate phenomena.
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fncel-15-693095 (1)
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Accepted/In Press date: 25 June 2021
e-pub ahead of print date: 3 September 2021
Published date: 3 September 2021
Additional Information:
Funding Information:
This work was supported by National Science Foundation (NSF) Grants 1557725 (to RM) and 1557820 (to MK), National Institute of Health (NIH) Award P30 EY003176 (to RK), NCRR P41 RR001395 (to PS), an LAS award for Faculty in the Natural Sciences from the University of Illinois at Chicago (to RM), an Indiana Wesleyan University Hodson Research Institute award (to MK), an Indiana Wesleyan University Scholar award (to MK), and a gift from the estate of John C. Hagensick (to RM).
Funding Information:
This work was supported by National Science Foundation (NSF) Grants 1557725 (to RM) and 1557820 (to MK), National Institute of Health (NIH) Award P30 EY003176 (to RK), NCRR P41 RR001395 (to PS), an LAS award for Faculty in the Natural Sciences from the University of Illinois at Chicago (to RM), an Indiana Wesleyan University Hodson Research Institute award (to MK), an Indiana Wesleyan University Scholar award (to MK), and a gift from the estate of John C. Hagensick (to RM).
Publisher Copyright:
© Copyright © 2021 Malchow, Tchernookova, Choi, Smith, Kramer and Kreitzer.
Keywords:
ATP, H, Müller cell, epilepsy, glia, migraine, pH, spreading depression
Identifiers
Local EPrints ID: 451522
URI: http://eprints.soton.ac.uk/id/eprint/451522
ISSN: 1662-5102
PURE UUID: 4b1f1f97-079e-4b7e-899b-c254c3c50f52
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Date deposited: 05 Oct 2021 16:33
Last modified: 17 Mar 2024 03:24
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Contributors
Author:
Robert P. Malchow
Author:
Boriana K. Tchernookova
Author:
Ji-in V Choi
Author:
Richard H. Kramer
Author:
Matthew A. Kreitzer
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