The Journal of Neuroscience, December 1991, 1 I(12): 36653694 Feature Article New Roles for Glia Barbara A. Barres Department of Biology, University College London, London WClE 6BT, England Recent findings suggest that glial cells, though lacking the ex- J. Burne, and M. Raff, unpublished observations). These cell citability usually associated with most neurons, may be more types are not thought to comprise all kinds of CNS glia; rather, actively involved in brain function than has been previously they may be restricted to the kinds of glia present in white thought. Collectively, these findings indicate that glial cells can matter. As shown in Table 1, each optic nerve glial cell type sense, and potentially respond to, a large array of neuronal sig- also expresses a characteristic set of voltage-dependent ion chan- nals. Because glial cells are intimately associated with most nel types in vitro. neurons, neurobiologists should reconsider the possible signif- In vivo, glial cells also possess characteristic ion channel phe- icance of active neuronal-glial signaling. notypes. For instance, if cells are studied immediately after preparation using a “tissue print” dissociation procedure, volt- Ion channels of glial cells age-dependent channels are observed in all rat optic nerve glia New studies, made possible with patch-clamp recording, have (Barres et al., 1990~). Tissue prints are prepared by gently blot- shown that glial cells in vitro and in situ possess most of the ting a small piece of enzymatically treated tissue against a sticky same kinds of voltage-dependent ion channels that are found nontoxic surface such as nitrocellulose-coated glass. This yields in neurons (reviewed in Barres et al., 1990a; Bevan, 1990). These a thin layer of viable optic nerve cells still bearing processes. findings were unexpected because earlier microelectrode re- Because the enzymes used to isolate the cells in this procedure cordings indicated that voltage-dependent conductances were do not digest any of the basic ion channel types and leave the not present in glial cells. These differences in findings are prob- cells with much of their surface area in the form of processes ably attributable to the different techniques used: the patch- intact, the observed types of ion channels probably reflect the clamp studies generally have been performed on isolated single in situ properties. As is true in vitro, each optic nerve glial cell cells, whereas the microelectrode recordings tended to be per- type studied in such tissue prints displays a distinct ion channel formed on cells in vitro and in situ that were highly coupled in phenotype (Table 1). a glial syncytium, which tends to obscure the presence of the Voltage-dependent Na+ and Ca*+ channels, which are tradi- voltage-dependent channels (for further discussion, see Ban-es tionally associated with excitability and neurotransmitter re- et al., 1990a). The horizontal neurons in the retina, which are lease, are frequently observed in acute glial preparations. For also extensively coupled in situ, were similarly long thought to instance, Na+ channels are ubiquitously present in astrocytes in be lacking voltage-dependent conductances. situ. An estimate of how densely packed these ion channels are Although a variety of glial preparations have been studied, in the membrane can be calculated by dividing the peak con- the basic findings are common and are exemplified by studies ductance by the cell surface area (surface area is generally de- of rat optic nerve glia (Barres et al., 1988a, 1990b,c). Cultures termined by measuring the cell’s capacitance in picofarads). In of cells isolated from postnatal optic nerves contain four types general, the densities of K+ channels in glial cells are similar to of macroglial cells that can be distinguished by their distinct those of neurons, while the densities of Na+ channels and Ca2+ antigenic phenotypes and morphologies: type 1 astrocytes, type channels in glia are considerably lower than those of neurons. 2 astrocytes, oligodendrocytes, and a progenitor cell, termed the An exception is the 02A progenitor cell, which has a density 02A progenitor (Raff et al., 1983a; Miller and Raff, 1984; re- of Na+ channels that approaches that found in neurons (Barres viewed in Miller et al., 1989a). The 02A progenitors are de- et al., 1990b). velopmentally bipotential, giving rise to both oligodendrocytes The properties of glial ion channels can differ from those of and type 2 astrocytes in vitro (Raff et al., 1983b, 1984). 02A neurons. Na+ channels in type 1 astrocytes, for example, open progenitors persist in adult animals (ffrench-Constant and Raff, at more negative potentials and open more slowly than Na+ 1986; Wolswijk and Noble, 1989) in large numbers (B. Fulton, channels in neurons in response to depolarization (Table 2; Barres et al., 1989). Their more negative voltage dependence suggests that the glial Na+ channels are specialized to detect the Correspondence should be addressed to Barbara A. Barres, Department of Bi- ology, University College London, Medawar Building B3, Gower Street, London more negative membrane potential that is found in glia. Sur- WClE 6BT, UK. prisingly, only the neuronal form of the Na+ channel is found Copyright 0 1991 Society for Neuroscience 0270-6474/91/l 13685-10$05.00/O in 02A progenitor cells (Table 2). An unresolved question is 3666 Barres * New Roles for Glia Table 1. Types of voltage-dependent ion channels found in rat optic nerve glia Retinal Type 2 ganglion Type 1 astrocytes astrocytes 02A progenitors Oligodendrocytes cells Culture Print Culture Culture Print Culture Print Suspension KR - + + - - + + - KD + + + + + + + + KA - - + + + + + + Na, - + + - - - - - Na, - - + + + - - + Ca, - + + - - - - + Ca, - + + - - - - + This table shows the presence (+) or absence (-) of various types of voltage-dependent ionic channels in rat optic nerve glial cells in culture and in tissue prints (tissue prints are prepared from blots of optic nerve and consist of acutely-isolated cells bearing processes, see text). Data are summarized from Barres et al. (1988a, 1989, 1990b, c). The ion channels observed in acutely isolated retinal ganglion cells are shown for comparison (Barres et al., 1988b, 1989). Only conductances observed in whole-cell recordings are shown. Abbreviations: K,,, inwardly rectifying potassium channel; KD, delayed-rectifying potassium channel; K,,, rapidly inactivating potassium channel; Na,, glial form of the sodium channel; Na, neuronal form of the sodium channel; Car, transient, rapidly inactivating calcium channel; Ca,, long-lasting, slowly inactivating calcium channel. Very minor current components, or current components found in only a small subset of cells, are not shown. whether the glial and neuronal forms of the Na+ channel are perhaps all, glial cells. In addition, it has been suggested that different proteins. ligand-gated channels might contribute to the resting conduc- Despite the presence of Na+ channels, the high resting con- tance of some glial cell types (Clark and Mobbs, 1992). ductance of most glial cell types in vitro and in situ appears to exclude any robust excitability, although single regenerative po- tentials can sometimes be elicited under experimental condi- Neurotransmitter receptors of glial cells tions where the resting potassium conductance is diminished. Glial cells in culture respond to a variety of neurotransmitters [It is possible, however, that the 02A progenitors are excitable with changes in membrane potential (reviewed by Bevan, 1990). in vivo, as they have a low resting conductance in addition to Until recently, it was not clear whether any of these changes are their high density of Na+ channels (Barres et al., 1989; 1990b).] mediated by opening of ligand-gated ion channels, or only by The lack of astrocyte and Schwann cell excitability has led Rit- the activation of electrogenic neurotransmitter uptake processes chic and his colleagues to hypothesize that glial cells might and by modulation of voltage-dependent channels known to be synthesize Na+ channel proteins for transfer to neurons (Bevan present in glia. New studies have demonstrated that most, if et al., 1985). That Na+ channels are thought to turn over rapidly not all, glial cells in vitro and in vivo express one or more types (reviewed in Ritchie, 1988) and that glial cells expressing Na+ of ligand-gated channels. channels come into close contact with nodes of Ranvier in both Glutamate- and GABA-gated ion channels are present in as- the CNS and PNS (Black et al., 1989; Suarez and Raff, 1989) trocytes in vitro (Bormann and Kettenmann, 1988; Sontheimer favor this hypothesis. That glial Na+ channels have properties et al., 1988; Usowicz et al., 1989; Cull-Candy and Wyllie, 199 1). different from those of neuronal channels (Barres et al., 1989; Detailed single-channel characterizations of GABA-gated Cl- Howe and Ritchie, 1990) argues against this hypothesis. Since channels in cortical type l-like astrocytes (Bormann and Ket- 02A progenitor cells persist in adult animals and have the neu- tenmann, 1988), and of glutamate-gated cation channels in 02A ronal form of the Na+ channel, they are a potential source of progenitors and type 2 astrocytes (Usowicz et al., 1989), show neuronal Na+ channel proteins (Table 2; ffrench-Constant and that these channels are similar to their neuronal counterparts. Raff, 1986); it is not known, however, whether the processes of Wyllie et al. (199 1) have carefully dissected the components 02A progenitors