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(The FASEB Journal. 2003;17:341-348.)
© 2003 FASEB

Glial neuronal signaling in the central nervous system

ELISABETH HANSSON1 and LARS RÖNNBÄCK

Institute of Clinical Neuroscience, Göteborg University, Göteborg, Sweden

1Correspondence: Institute of Clinical Neuroscience, Göteborg University, Medicinaregatan 5, P.O. Box 420, SE 405 30 Göteborg, Sweden. E-mail: elisabeth.hansson{at}anatcell.gu.se


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PHYSIOLOGICAL ACTIVITY
 PATHOLOGICAL CONDITIONS
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
Glial cells are known to interact extensively with neuronal elements in the brain, influencing their activity. Astrocytes associated with synapses integrate neuronal inputs and release transmitters that modulate synaptic sensitivity. Glial cells participate in formation and rebuilding of synapses and play a prominent role in protection and repair of nervous tissue after damage. For glial cells to take an active part in plastic alterations under physiological conditions and pathological disturbances, extensive specific signaling, both within single cells and between cells, is required. In recent years, intensive research has led to our first insight into this signaling. We know there are active connections between astrocytes in the form of networks promoting Ca2+ and ATP signaling; we also know there is intense signaling between astrocytes, microglia, oligodendrocytes, and neurons, with an array of molecules acting as signaling substances. The cells must be functionally integrated to facilitate the enormous dynamics of and capacity for reconstruction within the nervous system. In this paper, we summarize some basic data on glial neuronal signaling to provide insight into synaptic modulation and reconstruction in physiology and protection and repair after damage.—Hansson, E., Rönnbäck, L. Glial neuronal signaling in the central nervous system.


Key Words: astrocyte • microglia • oligodendrocyte • neuron • network • communication


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PHYSIOLOGICAL ACTIVITY
 PATHOLOGICAL CONDITIONS
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
NEURONS HAVE LONGbeen known to signal to each other by various kinds of transmitter substances. Recent data have revealed that glial activity is probably determined by neuronal activity and that glial cells have the capacity to signal not only to each other, but also back to the neurons. The majority of glial cells of the gray matter of the central nervous system (CNS) are protoplasmic astrocytes. They are thought to play many important and diverse roles including guiding development (1 , 2) , regulating extracellular concentrations of ions, metabolites, and neurotransmitters (3 4 5) , and supporting neuronal and synaptic function (6 , 7) .

Morphologically, protoplasmic astrocytes are closely associated with neurons. They can encase synaptic terminals, make extensive contact with endothelial cells from capillaries, and are interconnected with one another by gap junctions (8) . Oligodendrocytes form myelin, the substance that facilitates action potential propagation in the CNS. The cells express receptors and can respond to external stimuli with Ca2+ signaling. They synthesize an array of trophic factors and appear to be sensitive to neurotrauma (9 , 10) . Resting microglia direct small processes toward blood vessels, other glia, and neuronal elements. The cells are thought to register composition and concentration of ions, amino acids, and other signaling molecules in the extracellular milieu, sense signs of damage to other cells, and act accordingly (11) .


   PHYSIOLOGICAL ACTIVITY
TOP
 ABSTRACT
 INTRODUCTION
 PHYSIOLOGICAL ACTIVITY
PATHOLOGICAL CONDITIONS
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
Signals in the astroglial network
Glial Ca2+ signaling can be regarded as a form of glial excitability. Calcium-mediated signaling is one of the mechanisms by which CNS cells communicate with and modulate the activity of adjacent cells (12) . More than 12 years ago it was shown that mechanical stimulation of an astrocyte, as well as glutamate stimulation, can cause a local elevation of astrocytic Ca2+ or oscillating elevations that subsequently spreads to its neighbors in the form of a wave of elevated Ca2+ (13 14 15 16) (Fig. 1 , 1).It was observed that the Ca2+ waves can propagate at a rate of ~100 µm/s.



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  		Figure 1. Astrocytes (red) occupy a strategic position between the vasculature and the synapses (left). They also monitor glutamatergic neuronal activity, for instance, via activation of metabotropic glutamate receptors (mGluRs) (1), with a resultant Ca2+ signaling within the gap junction-coupled astrocytes (2). With the aid of ATP signaling, Ca2+ transients in the form of Ca2+ waves or oscillations can be induced in astrocytes even at some distance from the cells originally activated (3). Upon Ca2+ oscillations, excitatory amino acids like glutamate (Glu) and aspartate (Asp) are released by astrocytes and modulate synaptic activity (4). Even glutamate "spillover" from one synaptic region to another contributes to the modulation of synaptic activity. ATP released from astrocytes (5) promotes microglia (green) and astrocytes to release trophic factors such as basic fibroblast growth factor (bFGF), nerve growth factor (NGF), neurotrophin-3 (NT-3), ciliary neurotrophic factor (CNTF), and S100ß, promoting neuroplasticity (6). Vasoactive intestinal peptide (VIP) released from depolarized neurons (depicted in white) interacts with astrocytes and induces production and release of astroglial-derived neurotrophic factor (ADNF) (7).

The events underlying astrocytic Ca2+ wave propagation have been the focus of several studies of possible cellular mechanisms. Calcium elevations in astrocytes result from release of Ca2+ from intracellular stores, activated by elevations of the second messenger inositol-1,4,5-trisphosphate (IP3) (Fig. 1 , 2). This messenger is generated as a consequence of the activity of phospholipase C, which in turn is activated by certain G-protein-coupled receptors. Calcium waves were first thought to spread as a result of gap junction-mediated metabolic coupling between astrocytes in the form of IP3 (17) . Later studies indicated that in addition to diffusion of IP3 other mechanisms underlie the propagation of astrocyte Ca2+ waves, and the involvement of an extracellular component in the intercellular Ca2+ wave was suggested (18) . Calcium waves can pass frequently between disconnected cells as long as the gap between them does not exceed ~120 µm. The extracellular component is likely to be ATP (19 , 20) (Fig. 1 , 3). ATP release appears to be an important component of long-range Ca2+ signaling, whereas shorter range signaling may be mediated by metabolic coupling through gap junctions. There seems to be a tightly coordinated regulation of the gap junction and ATP-mediated signaling pathways by molecules such as endothelin, glutamate, anandamide, interleukin-1ß (IL-1ß), and {alpha}1-adrenergic agonists (21 22 23 24 25 26) .

Analyses of superfusates from astrocytic cultures have shown that ligands that evoke Ca2+ elevations can cause the release of excitatory amino acids such as glutamate or aspartate (27 28 29) (Fig. 1 , 4) and ATP (20) (Fig. 1 , 5). Coactivation of {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate and metabotropic glutamate receptors on astrocytes stimulates these cells to release glutamate through a Ca2+-dependent process mediated by prostaglandins. Three possible mechanisms behind this release process have been proposed: reverse operation of glutamate transporters; an anion channel-dependent pathway induced by swelling; and Ca2+-dependent exocytosis (30) . Astrocytes express high levels of glutamate transporters that normally function to clear glutamate from the extracellular space, especially in the vicinity of the synapse (31) . Under conditions of depolarization or when the Na+/K+ electrochemical gradient used by these transporters has been reversed, glutamate can be released through these transporters (32) . Swelling can lead to significant liberation of glutamate from astrocytes (33) . Evidence supporting Ca2+-dependent release of glutamate from astrocytes mediated by a vesicular mechanism is provided by Carmignoto et al. (34) .

Signals between astrocytes and neurons
Because astrocytes are intimately associated with the synapse, enwrapping many pre- and postsynaptic terminals, and are in close contact with the capillaries, they are in a position to shuffle nutrients and metabolites between the blood supply and the active neuron. They therefore play an active metabolic role in the CNS. Astrocytes can transfer information to neighboring neurons because a single astrocyte can have contact with multiple neurons (8) (Fig. 1) . An early observation was that neuronal activity can depolarize astrocytes (35) . This depolarization results from redistribution of extracellular K+, which must be taken away by astrocytes by channel- and carrier-mediated accumulation of K+ (36) .

Coordination of neuronal and glial activity requires that appropriate signals pass from one cell type to the other. This interaction may involve short-term functions such as ion regulation, release of substances, or transmitter clearance. A major question is how changes in glial [Ca2+]i serve to couple neuronal and glial functions. Intercellular Ca2+ waves can propagate between astrocytes and neurons (37 38 39) . Transmitters released by neurons induce transient elevations of internal Ca2+ levels in astrocytes, which were first studied in cell culture and later in brain slices. The list of transmitters that can mobilize astrocytic Ca2+ is almost as long as the list of molecules that activate neuronal receptors (40 41 42) . Among the transmitters or signal molecules that can induce elevations of astrocytic Ca2+ are glutamate (43) , norepinephrine (23) , 5-hydroxytryptamine (5-HT) (44) , histamine (45) , acetylcholine (45) , ATP (20) , gamma-aminobutyric acid (GABA) (46) , and endothelin (25) .

Elevation of astrocytic Ca2+ triggers the release of chemical transmitters from astrocytes, which can cause sustained modulatory actions on neighboring neurons. Nevertheless, the question remains: What is the target of action of transmitters released by astrocytes?

Regulation of Ca2+ waves in astrocytes may be important in the formation of synapses (2) . Astrocytes that can release glutamate and ATP are intimately associated with synapses, and it is therefore tempting to speculate that astrocytes could locally modulate the synapse through release of transmitters (8 , 47) . The released glutamate activates N-methyl-D-aspartate (NMDA) receptors on neighboring neurons, leading to neuronal Ca2+ transients and depolarization (48) .

In the developing brain, secreted factors from neurons and astrocytes may regulate synaptogenesis. The regulatory peptide in the CNS, vasoactive intestinal peptide (VIP), is thought to stimulate astrocytes to generate neurotrophic factors, the most potent and neuroprotective protein of which seems to be activity-dependent neurotrophic factor (ADNF) (49) (Fig. 1 , 7). This ADNF then acts directly on neurons to promote glutamate responses and morphological development. In the adult nervous system, this may be important in learning and behavioral processes. ADNF causes secretion of neurotrophin 3 (NT-3) and regulates NMDA receptor subunits 2A and 2B (50) . It is well known that astrocytes express VIP receptors with cyclic adenosine monophosphate (AMP) as second messenger (51) . Interaction takes place between cyclic AMP-activated ß receptors on astrocytes and VIP receptors, which results in a decrease in cyclic AMP level (52) . It could be speculated that the ß receptors regulate secretion of neurotrophic factors by astrocytes and thus influence neurons and possibly microglia.

Signals between astrocytes and microglia
Resting microglia show a down-regulated immunophenotype adapted to the specialized microenvironment of the CNS. They are small cells with a variable number of branching processes. Microglia respond not only to changes in the structural integrity of the brain, but also to very subtle alterations in their microenvironment. They have membrane receptors for several transmitters (11 , 53) and potassium channels (54) ; upon stimulation, they can release several cytokines (55 , 56) (Fig. 1 , 6); together with astrocytes, they release trophic factors such as basic fibroblast growth factor (bFGF), nerve growth factor (NGF), NT-3, ciliary neurotrophic factor, and S100ß, promoting neuroplasticity. Their ability to respond selectively to molecules involved in neurotransmission allows them to stay in their resting state to continuously register the physiological integrity of their microenvironment and react rapidly in the event of pathological disturbances. Microglia have purinergic receptors (53) that are stimulated by ATP, resulting in a [Ca2+]i increase (Fig. 1 , 5). There is a delayed [Ca2+]i increase in microglia after astrocyte stimulation and release of ATP. This could be interpreted as ATP mediating a form of Ca2+ communication between astrocytes and microglia (57) . Astrocytes seem to play an important regulatory role in the processes of microglial differentiation and deactivation. Several factors released by astrocytes—transforming growth factor-ß (TGF-ß), macrophage colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor—can induce ramification and up-regulation of delayed-rectifier outward K+ currents (K+DR) in microglia (58) . Astrocytes are capable of suppressing microglial phagocytosis (59) and production of the proinflammatory cytokine IL-12 (60) .

Signals between oligodendrocytes and neurons
New data indicate that even oligodendrocytes, the myelinating cells of the CNS, act as growth factor providers. Oligodendrocytes synthesize defined growth factors and provide trophic signals to nearby neurons. Examples of these factors are brain-derived neurotrophic factor, NT-3, insulin-like growth factor-1 (61) , and TGF-ß (62) . The expression of ion channels and receptors linked to Ca2+ signaling at different stages of development and myelination (10) and the specific roles of oligodendrocyte function must be investigated to determine how they may regulate proliferation, survival, and differentiation. Release of K+ or other neuroactive substances, e.g., GABA, from neurons may regulate oligodendroglial cell differentiation and myelin formation in white matter (63) .

Signals between astrocytes and endothelial cells
The blood-brain barrier is made up by endothelial cells. A large fraction of capillaries, but not their entire surface, is covered by astrocytic endfeet. Astrocytes are important for development of tight junctions between endothelial cells and may help regulate which compounds get into or out of the brain. This barrier property is generally seen as a mechanism for protecting the brain from unwanted actions of substances circulating in the blood (64) . Intercellular Ca2+ waves can be initiated in astrocytes and endothelial cells by mechanical, chemical, or electrical stimuli. Stimulation results in an increase in [Ca2+]i, which is propagated from cell to cell and can be two directional (65) . In response to increase in [Ca2+]i, the glucose transporter GLUT-1 present in astrocytes and endothelial cells increases its expression (66) .

A protein that is abundant in the CNS, especially in astrocytes and ependymal cells in osmosensory areas, is aquaporin-4 (AQP4) (67 , 68) . It has a highly polarized distribution, with marked expression in astrocyte endfeet that surround capillaries and form the glia limitans. Protein kinase C activator decreases expression of AQP4 mRNA in cultured astrocytes (69) . Little else is known about regulation of the protein's expression.


   PATHOLOGICAL CONDITIONS
TOP
 ABSTRACT
 INTRODUCTION
 PHYSIOLOGICAL ACTIVITY
 PATHOLOGICAL CONDITIONS
CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 
Neurotrauma
In neurotrauma, extracellular glutamate levels are increased and astrocytes are stimulated (Fig. 2 , 1), which results in increased [Ca2+]i and Ca2+ wave propagations. Dying cells may release nucleosides and nucleotides, which can stimulate proliferation of microglia (54) (Fig. 2 , 1). One characteristic of microglia is their early activation in response to injury. Microglia activation often precedes reactions of any other cell type in the brain. During neuronal damage or neurotrauma, they show a rapid transformation from the resting state to an activated state. These cells are round in shape and have an ameboid appearance without processes. The first stage of activation is a nonphagocytic state. During the second stage, microglia transform into fully activated phagocytic cells (11 , 54) .



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  		Figure 2. After brain damage (left), nucleosides, nucleotides, and glutamate (Glu) are released from the damaged region (1). These substances induce microglial proliferation and activation of microglia (green) and astrocytes (red) (2), with a resultant production of an array of molecules, including cytokines. Interleukin-1ß (IL-1ß) decreases connexin 43 expression (3) and thereby astroglial gap junction coupling. Tumor necrosis factor-{alpha} (TNF-{alpha}) reduces astroglial glutamate uptake capacity (4). K+ released by microglia and astrocytes induces a further decrease in astroglial glutamate uptake capacity (5). Microglia are able to produce and release really toxic substances such as free radicals, superoxide radicals (O2-), and nitric oxide (NO) (6) to participate in cytotoxic reactions. Transforming growth factor-ß (TGF-ß) inhibits the release of TNF-{alpha} (7), and VIP (8) released by depolarized neurons inhibits microglial cytokine production and induces synthesis of ADNF and NT-3 with the ability to modify subtypes of the NMDA receptor (9). Adenosine released from astrocytes (10) stimulates the production of trophic factors such as bFGF, NGF, and IL-1, important in rebuilding of the nervous system (11), and thereby participates in protective mechanisms. ß-Receptor agonists inhibit microglial production and release of cytokines. (Neurons are shown in white.)

ATP is an important molecule in activity-dependent signaling between neurons and glia at the synapse and in nonsynaptic regions. With an internal ATP concentration as high as 3–5 mM, astrocytes can, upon cellular damage, release large amounts of ATP into the extracellular environment (70) . Such ATP release may be important in triggering cellular responses to trauma and ischemia by initiating and maintaining reactive astrogliosis, which involves striking changes in astrocyte proliferation and morphology (71) (Fig. 2 , 2). ATP induces excessive depolarization by ligand-activated cationic channel P2X purinoceptors, which may be counteracted by outwardly rectifying K+ channels and by hyperpolarizing P2Y purinoceptors in nonproliferating microglia. Not all the responses to ATP released during brain injury are neuroprotective, however; in some cases, ATP contributes to the pathophysiology initiated after trauma. Treatment of cultured astrocytes with cytokines such as IL-1ß enhances the ATP-evoked release of arachidonic acid via P2Y2 receptors and cytosolic phospholipase A2. This may contribute to the neuronal loss associated with cerebral ischemia or traumatic brain injury (72) .

Reactive microglia secrete cytokines, including tumor necrosis factor-{alpha} (TNF-{alpha}) and IL-1ß, which can affect synaptic transmission and have trophic effects on neurons (56) . They can promote neurodegeneration (73 , 74) . The cytokines IL-1ß, interferon-{gamma} (IFN-{gamma}), and TNF-{alpha} are likely to be important for microglial activation because they can affect proliferation and immunophenotypical/functional changes in cultured microglial cells (75) . The release of IL-1ß leads to inhibition of Ca2+ waves in the astrocytic network, especially via the gap junction-mediated pathway because there appears to be a down-regulation of connexin 43 (Cx43) mRNA expression (24) (Fig. 2 , 3). In CNS injury, the proinflammatory cytokine TNF-{alpha} is up-regulated and released by astrocytes (75) and microglia (55) (Fig. 2 [4]). The release causes acute CNS insult by promoting gliosis (76) , inhibiting astrocytic glutamate uptake (77) , and inducing apoptosis, particularly in oligodendrocytes (9) . Up-regulation of K+DR and voltage-dependent inward Na+ channels (78) on microglia is seen, and an excessive extracellular K+ concentration leads to depolarization of astrocytes. Astrocytic glutamate uptake is inhibited (Fig. 2 [5]). On the other hand, activated microglia can express the glutamate transporter GLT-1 (79) . The cyclic AMP-mediated action of VIP seems to reduce TNF-{alpha} release at least by microglia (80) . Upon depolarization, VIP is released by neurons and binds to neighboring astrocytes on high-affinity VIP receptors (81) (Fig. 2 [8]). Cyclic AMP is increased by VIP stimulation, which can mediate release of ADNF, a glial-derived neuroprotective polypeptide (81) . As mentioned, ADNF causes secretion of NT-3 and regulates NMDA receptors on neurons (50) (Fig. 2 [9]). ADNF decreases oxidative stress (82) . VIP-stimulated cyclic AMP increase can be down-regulated by ß receptor activation of astrocytes (52) (Fig. 2 [7]); the ß-adrenergic agonists appear to modulate or reduce IL-1 and TNF-{alpha} production by microglia. The cytokines TGF-ß1 and IL-4 down-regulate microglial cytotoxicity (83) . Microglial cells release short-lived cytotoxic factors such as nitric oxide (NO), superoxide radical, and quinolinate (84) ; free oxygen radicals released by them could have a neurotoxic effect (85) (Fig. 2 [6]). Microglial cells can release neuroprotective factors such as bFGF and NGF (Fig. 1 [6] and (Fig. 2 [11]).

Another signaling substance of interest in physiology and injury is adenosine. This molecule is secreted from astrocytes and can exert a positive influence on nerve tissue repair (Fig. 2 [10]). Upon adenosine stimulation, astrocytes and microglia release trophic factors (Fig. 2 [11]). Furthermore, adenosine enhances astroglial glutamate uptake capacity (86) . It is well known that microglia communicate with each other and with other brain cells through specific extracellular signals such as cytokines and neurotransmitters (11) . Resting microglia in vivo and in vitro was not observed to show gap junction communication and be immunoreactive for Cx43. In stab wounds and in culture where microglia were treated with the immunostimulant bacterial lipopolysaccharide or the cytokines IFN-{gamma} and TNF-{alpha}, induced dye coupling and increased levels of Cx43 were observed (87) .

Swelling of astrocytes
Swelling of astrocytes is part of the cytotoxic or cellular edema response that characterizes brain damage in neurotrauma and is a major cause of morbidity and mortality (88 , 89) . Several mediators initiate swelling of astrocytes including elevation of extracellular K+, acidosis, release of neurotransmitters, and free fatty acids; both glutamate and ethanol induce swelling (90 91 92 93 94) . Inhibition of ATP synthesis causes glial cell swelling and, if sufficiently severe, plasma membrane disruption and cell death (95) . The predominant pathway for regulatory volume decrease is the opening of K+ channels and anion channels. The K+ channels involved are usually Ca2+-activated K+ channels (96) ; anion channels involved are mainly Cl- channels (97) . Astrocytic Cl- currents appear to be modulated by changes in [Ca2+]i and [ATP]i, which also influence polymerization of actin (98) .

Protective and cytotoxic roles
Whether activated microglia promote neuronal death or neuronal survival remains controversial. Many reports maintain that microglia induce a neurotoxic effect, secreting NO (99) (Fig. 2 [6]) and toxic cytokines (100) . On the other hand, many reports claim that microglia protect neurons in the damaged brain by secreting cytokines such as IL-1ß (101) , IL-6 (102) , TGF-ß (11) , bFGF (103) , and TNF-{alpha} (104) . In traumatic situations, microglia are activated much sooner than astrocytes (105) .

Giulian et al. (55) suggest that microglia are activated by phagocytic signals and produce neurotoxic factors that extend tissue damage during acute inflammatory responses in the CNS. At the same time, microglia-derived growth factors support astrocytes and have a promoting effect on neuronal survival.


   CONCLUSIONS AND PERSPECTIVES
TOP
 ABSTRACT
 INTRODUCTION
 PHYSIOLOGICAL ACTIVITY
 PATHOLOGICAL CONDITIONS
 CONCLUSIONS AND PERSPECTIVES
REFERENCES
 
It is important to understand the cellular signaling underlying plasticity of the CNS in physiological conditions and in functional disturbance after damage and in disease. It is now well known that neurons signal not only to each other but also to glial cells, informing the astroglial networks about neuronal activity and enabling them to support neurons metabolically and trophically, according to their specific requirements. Astroglial cells signal back to neurons and modulate synaptic activity. However, there is more to their function. We know today that astroglia aided by ATP can promote long-distance signaling from one network to another, even if the two networks are not coupled. Thus, synaptic sensitivity could be modulated even with no cellular bridges between synaptic regions. ATP is an important signal substance for neurons and astroglial cells to keep in contact with microglial cells. Under physiological conditions, microglia synthesize and release trophic factors; however, as soon as there is a functional disturbance of any kind in the CNS, microglia react, proliferate, and express protective or, in some situations, cytotoxic properties. The cells participate in restorative work, often in conjunction with astroglial cells. It is very important to identify intercellular signaling that mediates protective and restorative processes. By reinforcing such signaling upon tissue damage or during degeneration, it would be possible to limit the extent of permanent damage of nervous tissue.


   ACKNOWLEDGMENTS
 
The work performed in the authors’ laboratory was supported by grants from the Swedish Research Council (project no. 33X-06812 and 21X-13015), Edith Jacobson’s Foundation, and the Swedish Council for Working Life and Social Research. The technical assistance of the authors’ research by Ulrika Björklund and Barbro Eriksson is greatly appreciated. The figures were made by Eva Kraft, Göteborg, Sweden.

Received for publication May 6, 2002. Accepted for publication November 22, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PHYSIOLOGICAL ACTIVITY
 PATHOLOGICAL CONDITIONS
 CONCLUSIONS AND PERSPECTIVES
 REFERENCES
 

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