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172 Chapter 10
array of normal properties form rapidly in culture and in developing animals.72 It therefore
seems unlikely that “synapses might neither form nor function if there were no glia.”73
Effects of Neuronal Activity on Glial Cells
Potassium Accumulation in Extracellular Space
72
Williams, P. R. et al. 2010. J. Neurosci. 30:
11951–11961.
73
Pfrieger, F. W., and Barres, B. A. 1996. Curr.
Opin. Neurobiol. 6: 615–621.
74
Orkand, R. K., Nicholls, J. G., and Kuffler,
S. W. 1966. J. Neurophysiol. 29: 788–806.
75
Ransom, B. R., and Goldring, S. 1973.
J. Neurophysiol. 36: 869–878.
76
Van Essen, D, and Kelly, J.1973. Nature
241: 403–405.
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Schummers, J., Yu, H., and Sur, M. 2008.
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That nerve activity can depolarize glial cells is illustrated by experiments shown in Figure
10.12. The recordings were made from a glial cell in the optic nerve of the mud puppy
(Necturus). Action potentials that are initiated in the nerve fibers by electrical stimulation
or by flashes of light travel past the impaled glial cell, which becomes depolarized.74 The
depolarization is graded. Similarly, in the mammalian cortex, glial cells become depolarized
depending on the number of nerve fibers activated and on the frequency when neurons in
their vicinity are activated by stimulation of neural tracts, peripheral nerves, the surface of
the cortex, or sensory input.75 Astrocytes within an orientation column of the visual cortex
are depolarized by visual stimuli of the appropriate orientation.76 77
The cause of glial depolarization is potassium efflux from axons. When potassium accumulates in the intercellular clefts, it changes the [K]o/[K]i ratio and alters the membrane
potential of glial cells.
Changes in membrane potential in glial cells indicate the level of impulse traffic in
their environment. Potassium signaling between neurons and glia is different from that in
specific synaptic activity. Synaptic actions are confined to specialized regions on neuronal
cell bodies and dendrites, and they may be excitatory or inhibitory. In contrast, signaling by
potassium is not confined to structures containing receptors but occurs anywhere the glial
cell is exposed to potassium. Neurons exposed to increased external potassium concentrations become less depolarized than glia because the neuronal membrane deviates from the
Nernst equation in the physiological range (see Chapter 6).
Potassium and Calcium Movement through Glial Cells
Currents flow between regions of a cell that are at different potentials. Nerve cells, of course,
use this as the mechanism for conduction: current flows between inactive regions of an axon
Glial cell
(A)
Optic nerve
of Necturus
Recording arrangement
(B)
–82
Microelectrode in glial
cell of optic nerve
–84
–86
–88
0
3
6
Time (s)
9
Glial cell membrane
potential (mV)
Glial cell membrane
potential (mV)
Single stimuli to axons
FIGURE 10.12 Effect of Action Potentials on Glial Cells in mud
puppy optic nerve. (A) Synchronous impulses evoked by electrical
stimulation of nerve fibers cause glial cells to become depolarized. The
amplitude of the potentials depends on the number of axons activated
and on the frequency of stimulation. (B) Illumination of the eye with a
0.1 second flash of light causes depolarization of a glial cell in the optic
nerve of an anesthetized mud puppy with intact circulation. Lower trace
monitors light stimulus. (After Orkand, Nicholls, and Kuffler, 1966.)
– 80
– 90
Light
0
5
10
Time (s)
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or disseminated in any form without express written permission from the publisher.
15
20
Properties and Functions of Neuroglial Cells 173
0 seconds
0.2 seconds
1.5 seconds
3.5 seconds
5.5 seconds
9.5 seconds
FIGURE 10.13 Calcium Wave Propagated through Retinal Glial Cells. Pseudocolor images
of Ca2+ fluorescence within astrocytes (larger cells) and Müller cells (smaller spots) at the vitreal
surface of the retina. Red represents the highest intensity and blue, the lowest. The Ca2+ wave
is evoked by a mechanical stimulus to a single astrocyte. The wave is initiated at the stimulated
cell (top panel, middle) and propagates outward through neighboring astrocytes and Müller cells.
Elapsed times following stimulation are noted at the top of each panel. (Used with permission
from E. A. Newman, unpublished.)
50 μm
and the region that is occupied by a nerve impulse. Since glial cells are linked to each other
by low-resistance connections,14 their conducting properties are similar to those of a single,
elongated cell. Consequently, if several glial cells become depolarized by increased potassium
concentrations in their environment, they draw current from the unaffected cells. Similarly,
an elongated Müller cell that extends through the thickness of the retina generates current
when the potassium concentration increases locally over part of its surface (Figure 10.13;
see also Figure 10.5). Inward current in the region of raised [K]o, carried by potassium ions,
spreads to other regions of the glial cell and through gap junctions to other glial cells. Currents generated by glial cells contribute to recordings made from the eye or the skull with
extracellular electrodes. Such recordings, known as the electroretinogram (ERG) and the
electroencephalogram (EEG) are valuable for the clinical diagnosis of pathological conditions.
Calcium Waves in Glial Cells
In networks of glial cells in culture or in situ, transient increases in cytoplasmic calcium
concentration arise by release from intracellular stores (see Figure 10.13). Using fluorescent
indicators, one can observe such oscillatory waves of increased calcium concentration as
they propagate from glial cell to glial cell through intercellular junctions.78 Pannexins, or
hemi-junctions permeable to ATP, are present in extrajunctional glial cell membranes. As a
result, ATP leaks out of activated glial cells into extracellular space.31 Calcium waves occur
spontaneously79 or can be triggered by depolarization, by transmitters such as ATP,29 or by
mechanical stimulation. They resemble the calcium waves seen in neuronal networks and in
epithelial cells.80 Propagating intracellular calcium waves that trigger the release of ATP or
glutamate can influence neuronal firing patterns (see below). There is evidence that calcium
waves in cortical radial glia modulate the production of neurons during development.81
78
Metea, M. R., and Newman, E. A. 2006. Glia
54: 650–655.
79
Kurth-Nelson, Z. L., Mishra, A., and Newman,
E. A. 2009. J. Neurosci. 29: 11339–11346.
80
Oheim, M., Kirchhoff, F., and Stühmer, W.
2006. Cell Calcium 40: 423–439.
81
Weissman, T. A. et al. 2004. Neuron 43:
647–661.
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or disseminated in any form without express written permission from the publisher.
174 Chapter 10
FIGURE 10.14 Potassium Currents in
Glial Cells. (A) The glial cells in the diagram
are linked by gap junctions. Potassium
released by active axons in one region depolarizes the glial cell and enters it, causing current flow and outward movement
of potassium through potassium channels
elsewhere in the glial tissue. The concept of
spatial buffering of potassium has been postulated as a mechanism for influencing neuronal function by glial cells. (B) Depolarization
of the glial cell can cause calcium waves that
spread through the network. The raised intracellular calcium concentration allows ATP to
leak out from the glia through hemichannels
(see Chapter 8).
(A)
K+ out
K+
K+
K+
K+
K+
K+
K+ out
K+ in
Glial
cell
Active neurons
Gap junctions
(B)
Hemi-connexons
ATP out
K+
K+
K+
K+
K+
K+
Ca2+
Active neurons
ATP out
ATP out
Ca2+
Ca2+
Gap junctions
Spatial Buffering of Extracellular Potassium Concentration by Glia
One obvious property of glial cells is to separate and group neuronal processes. As a result,
the potassium concentration increases around some neurons while others in a separate
compartment are protected. An attractive concept is that glial cells regulate the potassium
concentration in intercellular clefts, a process known as spatial buffering.19,82 According to
this hypothesis, glial cells act as conduits for uptake of potassium from the clefts to preserve
the constancy of the environment.83 Since glial cells are coupled to each other, potassium
enters in one region and leaves at another, as already described (Figure 10.14). That potassium will move through glial cells as a consequence of potassium buildup is inevitable. It
is, however, not simple to estimate quantitatively how much potassium actually moves or
how much these movements reduce the extracellular potassium concentration. For such
calculations, numerous assumptions about geometry, conductance, diffusion, and active
transport of potassium into neurons and glial cells must be made.84
Glial Cells and Neurotransmitters
82
Kofuji, P., and Newman, E. A. 2004.
Neuroscience 129: 1045–1056.
83
Kofuji, P. et al. 2000. J. Neurosci. 20:
5733–5740.
84
Odette, L. L., and Newman, E. A. 1988. Glia
1: 198–210.
85
D’Antoni, S. et al. 2008. Neurochem. Res.
33: 2436–2443.
86
Qian, H. et al. 1996. Proc. R. Soc. Lond. B,
Biol. Sci. 263: 791–796.
87
Furness, D. N. et al. 2008. Neuroscience
157: 80–94.
88
Takeda, H., Inazu, M., and Matsumiya,T.
2002. Naunyn Schmiedebergs Arch
Pharmacol. 366: 620–623.
89
Gomeza, J. et al. 2003. Neuron 40: 785–796.
Transmitters such as GABA, glutamate, glycine, purines, and acetylcholine act on glial membranes to produce depolarizing or hyperpolarizing responses.1,28,29,85,86 Figure 10.15 shows
activation of GABAA receptors by GABA in retinal Müller cells. These GABA receptors are
similar to those of neurons in many respects. Similarly, glial cell membranes contain receptors
for ATP and glutamate, which depolarize, allow calcium to enter, and initiate calcium waves.
Glial cells play a key role in transmitter uptake in the CNS, under normal and pathological
conditions. The extracellular concentration of a transmitter such as glutamate, norepinephrine,
or glycine that has been released at synapses is reduced in part by diffusion away from the site
of release, but mainly by uptake into neurons and into glial cells.87–89 As in neurons, glutamate
transport in glial cells is coupled to inward movement of sodium along its electrochemical gradient (see Chapter 9). In the absence of a removal mechanism, excessively high levels of external
glutamate can activate N-methyl-D-aspartate (NMDA) receptors in neurons, which in turn can
lead to calcium entry and cell death. Quantitative estimates indicate that glial cell transport
plays a key role in preventing such excessive rises in extracellular glutamate concentration.
Release of Transmitters by Glial Cells
If glial cells themselves become depolarized by raised extracellular potassium or by glutamate, or if intracellular sodium concentration is increased, their membranes transport
©2011 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured
or disseminated in any form without express written permission from the publisher.