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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. 77 Schummers, J., Yu, H., and Sur, M. 2008. Science 320:1638–1643. 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) ©2011 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured 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. ©2011 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured 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.