Medical Physiology, 3rd Edition

Glial Cells

Glial cells constitute half the volume of the brain and outnumber neurons

The three major types of glial cells in the CNS are astrocytes, oligodendrocytes, and microglial cells (Fig. 11-9Table 11-3). As discussed in Chapter 10, the peripheral nervous system (PNS) contains other, distinctive types of glial cells, including satellite cells, Schwann cells, and enteric glia. Glial cells represent about half the volume of the brain and are more numerous than neurons. Unlike neurons, which have little capacity to replace themselves when lost, neuroglial (or simply glial) cells can proliferate throughout life. An injury to the nervous system is the usual stimulus for proliferation.


FIGURE 11-9 Astrocytes. The endfeet of both fibrous and protoplasmic astrocytes abut the pia mater (see Fig. 11-2) and the capillaries (see Fig. 11-8B).

TABLE 11-3

Glial Cell Types







Fibrous astrocytes


White matter


Protoplasmic astrocytes


Gray matter

Weakly positive

Radial glial cells


Throughout brain during development


Müller cells




Bergmann glia




Ependymal cells


Ventricular lining




Mainly white matter


Microglial cells


Throughout brain


Satellite cells


Sensory and autonomic ganglia

Weakly positive

Schwann cells


Peripheral axons


Enteric glial cells


Gut wall


ENS, enteric nervous system.

Historically, glial cells were viewed as a type of CNS connective tissue whose main function was to provide support for the true functional cells of the brain, the neurons. This firmly entrenched concept remained virtually unquestioned for the better part of a century after the early description of these cells by Virchow in 1858. Knowledge about glial cells has accumulated slowly because these cells have proved far more difficult to study than neurons. Because glial cells do not exhibit easily recorded action potentials or synaptic potentials, these cells were sometimes referred to as silent cells. However, glial cells are now recognized as intimate partners with neurons in virtually every function of the brain.

Astrocytes supply fuel to neurons in the form of lactic acid

Astrocytes have great numbers of extremely elaborate processes that closely approach both blood vessels and neurons. This arrangement led to the idea that astrocytes transport substances between the blood and neurons. This notion may be true, but it has not been proved. Throughout the brain, astrocytes envelop neurons, and both cells bathe in a common BECF. Therefore, astrocytes are ideally positioned to modify and to control the immediate environment of neurons. Most astrocytes in the brain are traditionally subdivided into fibrous and protoplasmic types (see Table 11-3). Fibrous astrocytes (found mainly in white matter) have long, thin, and well-defined processes, whereas protoplasmic astrocytes (found mainly in gray matter) have shorter, frilly processes (see Fig. 11-9). Astrocytes are evenly spaced. In cortical regions, the dense processes of an individual astrocyte define its spatial domain, into which adjacent astrocytes do not encroach. The cytoskeleton of these and other types of astrocytes contains an identifying intermediate filament (see p. 23) that is composed of a unique protein called glial fibrillar acidic protein (GFAP). The basic physiological properties of both types of astrocyte are similar, but specialized features, such as the expression of neurotransmitter receptors, vary among astrocytes from different brain regions.

During development, another type of astrocyte called the radial glial cell (see pp. 263–265) is also present. As discussed on p. 267, these cells create an organized “scaffolding” by spanning the developing forebrain from the ventricle to the pial surface. Astrocytes in the retina and cerebellum are similar in appearance to radial glial cells. Like astrocytes elsewhere, these cells contain the intermediate filament GFAP. Retinal astrocytes, called Müller cells, are oriented so that they span the entire width of the retina. Bergmann glial cells in the cerebellum have processes that run parallel to the processes of Purkinje cells.

Astrocytes store virtually all the glycogen present in the adult brain. They also contain all the enzymes needed for metabolizing glycogen. The brain's high metabolic needs are primarily met by glucose transferred from blood because the brain's glucose supply in the form of glycogen is very limited. In the absence of glucose from blood, astrocytic glycogen could sustain the brain for only 5 to 10 minutes. As implied, astrocytes can share with neurons the energy stored in glycogen, but not by the direct release of glucose into the BECF. Instead, astrocytes break glycogen down to glucose and even further to lactate, which is transferred to nearby neurons where it can be aerobically metabolized (Fig. 11-10). The extent to which this metabolic interaction takes place under normal conditions is not known, but it may be important during periods of intense neuronal activity, when the demand for glucose exceeds the supply from blood.


FIGURE 11-10 Role of astrocytes in providing lactate as fuel for neurons. Neurons have two fuel sources. They can obtain glucose directly from the blood plasma or they can obtain lactate from astrocytes. In the direct path, the oxidation of one glucose molecule provides 30 ATP molecules to the neuron. In the transastrocyte path, conversion of two lactates to two pyruvates, and then the subsequent oxidation of the pyruvate, provides 28 molecules of ATP to the neuron. GLUT1 and GLUT3, glucose transporters 1 and 3; MCT1 and MCT2, monocarboxylate cotransporters 1 and 2.

Astrocytes can also provide fuel to neurons in the form of lactate derived directly from glucose, independent of glycogen. Glucose entering the brain from blood first encounters the astrocytic endfoot. Although it can diffuse past this point to neurons, glucose may be preferentially taken up by astrocytes and shuttled through astrocytic glycolysis to lactic acid, a significant portion of which is excreted into the BECF surrounding neurons. Several observations support the notion that astrocytes provide lactate to neurons. First, astrocytes have higher anaerobic metabolic rates and export much more lactate than do neurons. Second, neurons and their axons function normally when glucose is replaced by lactate, and some neurons seem to prefer lactate to glucose as fuel. Note that when they are aerobically metabolized, the two molecules of lactate derived from the breakdown of one molecule of glucose provide nearly as much ATP (28 molecules) as the complete oxidation of glucose itself (30 molecules of ATP; see Table 58-4). The advantage of this scheme for neuronal function is that it provides a form of substrate buffering, a second energy reservoir that is available to neurons. The availability of glucose in the neuronal microenvironment depends on moment-to-moment supply from the blood and varies as a result of changes in neural activity. The concentration of extracellular lactate, however, is buffered against such variability by the surrounding astrocytes, which continuously shuttle lactate to the BECF by metabolizing glucose or by breaking down glycogen.

Astrocytes are predominantly permeable to K+ and also help regulate [K+]o

The membrane potential of glial cells is more negative than that of neurons. For example, astrocytes have a Vm of about −85 mV, whereas the resting neuronal Vm is about −65 mV. Because the equilibrium potential for K+ is about −90 mV in both neurons and glia, the more negative Vm in astrocytes indicates that glial membranes have higher K+ selectivity than neuronal membranes do (see p. 148). Although glial cells express a variety of K+ channels, inwardly rectifying K+ channels seem to be important in setting the resting potential. These channels are voltage gated and are open at membrane potentials that are more negative than about −80 mV, close to the observed resting potential of astrocytes. Astrocytes express many other voltage-gated ion channels that were once thought to be restricted to neurons. The significance of voltage-gated Na+ and Ca2+ channels in glial cells is unknown. Because the ratio of Na+ to K+ channels is low in adult astrocytes, these cells are not capable of regenerative electrical responses such as the action potential.

One consequence of the higher K+ selectivity of astrocytes is that the Vm of astrocytes is far more sensitive than that of neurons to changes in [K+]o. For example, when [K+]o is raised from 4 to 20 mM, astrocytes depolarize by ~25 mV versus only ~5 mV for neurons. This relative insensitivity of neuronal resting potential to changes in [K+]o in the “physiological” range may have emerged as an adaptive feature that stabilizes the resting potential of neurons in the face of the transient increases in [K+]o that accompany neuronal activity. In contrast, natural stimulation, such as viewing visual targets of different shapes or orientations, can cause depolarizations of up to 10 mV in astrocytes of the visual cortex. The accumulation of extracellular K+ that is secondary to neural activity may serve as a signal—to glial cells—that is proportional to the extent of the activity. For example, small increases in [K+]o cause astrocytes to increase their glucose metabolism and to provide more lactate for active neurons. In addition, the depolarization that is triggered by the increased [K+]o leads to the influx of image into astrocytes by the electrogenic Na/HCO3 cotransporter (see p. 122); this influx of bicarbonate in turn causes a fall in extracellular pH that may diminish neuronal excitability. imageN11-4


Glial Modulation of Neuronal Excitability via Extracellular K+ and pH

Contributed by Mark Bevensee, Walter Boron, Bruce Ransom

Chesler and Ransom have proposed a model (eFig. 11-1) that integrates our knowledge of acid-base transporters in neurons and astrocytes, the pH sensitivity of neuronal ion channels, and a wealth of data on changes in the composition of BECF during neuronal activity (e.g., increased [K+]o that occurs as the result of a train of action potentials). Neural activity (step 1 in the figure) leads to a rise in [K+]BECF (step 2), which would depolarize astrocytes (step 3). As first described by Siebens in renal proximal-tubule cells, this depolarization would promote electrogenic Na/HCO3 influx (step 4), which simultaneously raises pHi and lowers pHBECF (step 5). The low pHBECF would inhibit the neuronal Na+-driven Cl-HCO3 exchanger (step 6), causing neuronal pHi to fall (step 7). The decreases in both pHBECF and neuronal pHicomplete the feedback loop by inhibiting voltage-gated channels and ligand-gated changes, thereby decreasing neuronal excitability (step 8). Indeed, low pH appears to reduce neuronal activity in experimental models of epilepsy.


EFIGURE 11-1 Glial modulation of neuronal excitability.


Chesler M. The regulation and modulation of pH in the nervous system. Prog Neurobiol. 1990;34:401–427.

Ransom BR. Glial modulation of neural excitability mediated by extracellular pH: A hypothesis. Prog Brain Res. 1992;94:37–46.

Siebens AW, Boron WF. Depolarization-induced alkalinization in proximal tubules. I. Characteristics and dependence on Na+Am J Physiol. 1989;25:F342–F353.

Siebens AW, Boron WF. Depolarization-induced alkalinization in proximal tubules. II. Effects of lactate and SITS. Am J Physiol. 1989;25:F354–F365.

Not only do astrocytes respond to changes in [K+]o, they also help regulate it (Fig. 11-11A). The need for homeostatic control of [K+]o is clear because changes in brain [K+]o can influence transmitter release, cerebral blood flow, cell volume, glucose metabolism, and neuronal activity. Active neurons lose K+ into the BECF, and the resulting increased [K+]o tends to act as a positive-feedback signal that increases excitability by further depolarizing neurons. This potentially unstable situation is opposed by efficient mechanisms that expedite K+ removal and limit its accumulation to a maximum level of 10 to 12 mM, the so-called ceiling level. [K+]o would rise far above this ceiling with intense neural activity if K+ clearance depended solely on passive redistribution of K+ in the BECF. Neurons and blood vessels can contribute to K+homeostasis, but glial mechanisms are probably most important. Astrocytes can take up K+ in response to elevated [K+]o by three major mechanisms: the Na-K pump, the Na/K/Cl cotransporter, and the uptake of K+ and Cl through channels. Conversely, when neural activity decreases, K+ and Cl leave the astrocytes through ion channels.


FIGURE 11-11 K+ handling by astrocytes.

Gap junctions couple astrocytes to one another, allowing diffusion of small solutes

The anatomical substrate for cell-cell coupling among astrocytes is the gap junction, which is composed of membrane proteins called connexins that form large aqueous pores connecting the cytoplasm of two adjacent cells (see pp. 158–159). Coupling between astrocytes is strong because hundreds of gap junction channels may be present between two astrocytes. Astrocytes may also be weakly coupled to oligodendrocytes. Ions and organic molecules that are up to 1 kDa in size, regardless of charge, can diffuse from one cell into another through these large channels. Thus, a broad range of biologically important molecules, including nucleotides, sugars, amino acids, small peptides, cAMP, Ca2+, and inositol 1,4,5-trisphosphate (IP3), have access to this pathway.

Gap junctions may coordinate the metabolic and electrical activities of cell populations, amplify the consequences of signal transduction, and control intrinsic proliferative capacity. The strong coupling among astrocytes ensures that all cells in the aggregate have similar intracellular concentrations of ions and small molecules and similar membrane potentials. Thus, the network of astrocytes functionally behaves like a syncytium, much like the myocytes in the heart (see p. 483). In ways that are not yet clear, gap junctional communication can be important for the control of cellular proliferation. The most common brain cell–derived tumors in the CNS arise from astrocytes. Malignant astrocyte tumors, like malignant neoplasms derived from other cells that are normally coupled (e.g., liver cells), lack gap junctions. imageN11-5



Contributed by Bruce Ransom

As pointed out in the text, malignant astrocyte tumors (i.e., astrocytomas) lack gap junctions. One theory is that growth-limiting factors pass among coupled cells to regulate proliferation. Thus, if gap junctions are lost, cells with minimal intrinsic production of these factors would be more prone to escape from normal regulation and become tumor clones.

The coupling among astrocytes may also play an important role in controlling [K+]o by a mechanism known as spatial buffering. The selective K+ permeability of glia, together with their low-resistance cell-cell connections, permits them to transport K+ from focal areas of high [K+]o, where a portion of the glial syncytium would be depolarized, to areas of normal [K+]o, where the glial syncytium would be more normally polarized (see Fig. 11-11B). Redistribution of K+ proceeds by way of a current loop in which K+ enters glial cells at the point of high [K+]o and leaves them at sites of normal [K+]o, with the extracellular flow of Na+completing this circuit. At a site of high neuronal activity, [K+]o might rise to 12 mM, which would produce a very large depolarization of an isolated, uncoupled astrocyte. However, because of the electrical coupling among astrocytes, the Vm of the affected astrocyte remains more negative than the equilibrium potential for K+ (EK) predicted for a [K+]o of 12 mM. Thus, K+ would tend to passively enter coupled astrocytes through channels at sites of high [K+]o. imageN11-6 As discussed in the preceding section, K+ may also enter the astrocyte by transporters.


K+ Siphoning by Müller Cells

Contributed by Bruce Ransom

An additional specialization that contributes to spatial buffering is a nonuniform distribution of K+ channels on a single cell. The density of K+ channels on the cell membrane of retinal Müller cells (eFig. 11-2A), which are specialized astrocytes, is highest on the cell's endfoot. Thus, focal increases in [K+]o at the endfoot cause greater depolarization than if they occur elsewhere along the cell's membrane (see eFig. 11-2B). Because the endfoot of the Müller cell, which abuts the vitreous humor of the eye, has the highest density of K+ channels, excess extracellular K+ is preferentially transported to the vitreous, which acts as a disposal site. It is not known whether nonuniform K+ channel distribution is a general feature of astrocytes.


EFIGURE 11-2 Role of Müller cells in spatial buffering. A, The Müller cells are the predominant glial cells of the retina. B, In an experiment on an isolated Müller cell from a salamander retina, the investigator monitored the membrane potential from the soma of the cell while ejecting K+ from a second pipette at different points along the Müller cell. These ejections, which raise local [K+]o, produced the largest depolarizations when K+ was ejected at the endfoot and microvilli.

Astrocytes synthesize neurotransmitters, take them up from the extracellular space, and have neurotransmitter receptors

Astrocytes synthesize at least 20 neuroactive compounds, including both glutamate and gamma-aminobutyric acid (GABA). Neurons can manufacture glutamate from glucose or from the immediate precursor molecule glutamine (Fig. 11-12). The glutamine pathway appears to be the primary one in the synthesis of synaptically released glutamate. Glutamine, however, is manufactured only in astrocytes by use of the astrocyte-specific enzyme glutamine synthetase to convert glutamate to glutamine. Astrocytes release this glutamine into the BECF through the SNAT3 and SNAT5 transporters (SLC38 family, see Table 5-4) for uptake by neurons through SNAT1 and SNAT2. Consistent with its role in the synthesis of glutamate for neurotransmission, glutamine synthetase is localized to astrocytic processes surrounding glutamatergic synapses. In the presynaptic terminals of neurons, glutaminase converts the glutamine to glutamate for release into the synaptic cleft by the presynaptic terminal. Finally, astrocytes take up much of the synaptically released glutamate to complete this glutamate-glutamine cycle. Disruption of this metabolic interaction between astrocytes and neurons can depress glutamate-dependent synaptic transmission.


FIGURE 11-12 Role of astrocytes in the glutamate-glutamine cycle. Most of the glutamate of glutamatergic neurons is generated from glutamine, which the neurons themselves cannot make. However, astrocytes take up some of the glutamate that is released at synapses (or produced by metabolism) and convert it into glutamine. The glutamine then enters the neuron, where it is converted back to glutamate. This glutamate also serves as the source for GABA in inhibitory neurons.

Glutamine derived from astrocytes is also important for synthesis of the brain's most prevalent inhibitory neurotransmitter, GABA. In the neuron, the enzyme glutamic acid decarboxylase converts glutamate (generated from glutamine) to GABA (see Fig. 13-8A). Because astrocytes play such an important role in the synthesis of synaptic transmitters, these glial cells are in a position to modulate synaptic efficacy.

Astrocytes have high-affinity uptake systems for the excitatory transmitter glutamate and the inhibitory transmitter GABA. In the case of glutamate uptake, mediated by EAAT1 and EAAT2 (SLC1 family, see Table 5-4), astrocytes appear to play the dominant role compared with neurons or other glial cells. Glutamate moves into cells accompanied by two Na+ ions and an H+ ion, with one K+ ion moving in the opposite direction (see Fig. 11-12). Because a net positive charge moves into the cell, glutamate uptake causes membrane depolarization. The presynaptic cytoplasm may contain glutamate at a concentration as high as 10 mM, and vesicles may contain as much as 100 mM glutamate. Nevertheless, the glutamate uptake systems can maintain extracellular glutamate at concentrations as low as ~1 µM, which is crucial for normal brain function.

Neurotransmitter uptake systems are important because they help terminate the action of synaptically released neurotransmitters. Astrocyte processes frequently surround synaptic junctions and are ideally placed for this function. Under pathological conditions in which transmembrane ion gradients break down, high-affinity uptake systems may work in reverse and release transmitters, such as glutamate, into the BECF (Box 11-4).

Box 11-4

Excitatory Amino Acids and Neurotoxicity

The dicarboxylic amino acid glutamate is the most prevalent excitatory neurotransmitter in the brain (see pp. 318–319). Although glutamate is present at millimolar levels inside neurons, the BECF has only micromolar levels of glutamate, except at sites of synaptic release (see Fig. 11-12). Excessive accumulation of glutamate in the BECF—induced by ischemia, anoxia, hypoglycemia, or trauma—can lead to neuronal injury. Astrocytes are intimately involved in the metabolism of glutamate and its safe disposition after synaptic release.

In anoxia and ischemia, the sharp drop in cellular levels of ATP inhibits the Na-K pump, which rapidly leads to large increases in [K+]o and [Na+]i. These changes result in membrane depolarization, with an initial burst of glutamate release from vesicles in presynaptic terminals. Vesicular release, however, requires cytoplasmic ATP and probably halts rapidly. The ability of astrocytes to remove glutamate from the BECF is impeded by the elevated [K+]o, elevated [Na+]i, and membrane depolarization. In fact, the unfavorable ion gradients can cause the transporter to run in reverse and dump glutamate into the BECF. The action of rising levels of extracellular glutamate on postsynaptic and astrocytic receptors reinforces the developing ionic derangements by opening channels permeable to Na+ and K+. This vicious cycle at the level of the astrocyte can rapidly cause extracellular glutamate to reach levels that are toxic to neurons—excitotoxicity.

Astrocytes express a wide variety of ionotropic and metabotropic neurotransmitter receptors that are similar or identical to those present on neuronal membranes. As in neurons, activation of these receptors can open ion channels or generate second messengers. In most astrocytes, glutamate produces depolarization by increasing Na+ permeability, whereas GABA hyperpolarizes cells by opening Cl channels, similar to the situation in neurons (see pp. 326–327). Transmitter substances released by neurons at synapses can diffuse in the BECF to activate nearby receptors on astrocytes, thus providing, at least theoretically, a form of neuronal-glial signaling.

Astrocytes apparently can actively enhance or depress neuronal discharge and synaptic transmission by releasing neurotransmitters that they have taken up or synthesized. The release mechanisms are diverse and include stimulation by certain neurotransmitters, a fall in [Ca2+]o, or depolarization by elevated [K+]o. Applying glutamate to cultured astrocytes increases [Ca2+]i, which may oscillate. Moreover, these increases in [Ca2+]i can travel in waves from astrocyte to astrocyte through gap junctions or through a propagated front of extracellular ATP release that activates astrocytic purinergic receptors, thereby increasing [Ca2+]i and releasing more ATP. These [Ca2+]i waves—perhaps by triggering the release of a neurotransmitter from the astrocyte—can lead to changes in the activity of nearby neurons. This interaction represents another form of glial-neuronal communication.

Astrocytes secrete trophic factors that promote neuronal survival and synaptogenesis

Astrocytes, and other glial cell types, are a source of important trophic factors and cytokines, including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), and ciliary neurotrophic factor (CNTF). Moreover, both neurons and glial cells express receptors for these molecules, which are crucial for neuronal survival, function, and repair. The expression of these substances and their cognate receptors can vary during development and with injury to the nervous system.

The development of fully functional excitatory synapses in the brain requires the presence of astrocytes, which act at least in part by secreting proteins called thrombospondins. Indeed, synapses in the developing CNS do not form in substantial numbers before the appearance of astrocytes. In the absence of astrocytes, only ~20% of the normal number of synapses form.

Astrocytic endfeet modulate cerebral blood flow

Astrocytic endfeet (see p. 286) surround not only capillaries but also small arteries. Neuronal activity can lead to astrocytic [Ca2+]i waves—as previously described on pages 291–292 that spread to the astrocytic endfeet, or to isolated increases in endfoot [Ca2+]i. In either case, the result is a rapid increase in blood vessel diameter and thus in local blood flow. A major mechanism of this vasodilation is the stimulation of phospholipase A2 in the astrocyte, the formation of arachidonic acid, and the liberation through cyclooxygenase 1 (see Fig. 3-11) of a potent vasodilator that acts on vascular smooth muscle. This is one mechanism of neuron-vascular coupling—a local increase in neuronal activity that leads to a local increase in blood flow. Radiologists exploit this physiological principle in a form of functional magnetic resonance imaging (fMRI) called blood oxygen level–dependent (BOLD) MRI, which uses blood flow as an index of neuronal activity.

Astrocytic modulation of blood flow is complex, and increases in [Ca2+]i in endfeet can sometimes lead to vasoconstriction.

Oligodendrocytes and Schwann cells make and sustain myelin

The primary function of oligodendrocytes as well as of their PNS equivalent, the Schwann cell, is to provide and to maintain myelin sheaths on axons of the central and peripheral nervous systems, respectively. As discussed on p. 199, myelin is the insulating “electrical tape” of the nervous system (see Fig. 7-21B). Oligodendrocytes are present in all areas of the CNS, although their morphological appearance is highly variable and depends on their location within the brain. In regions of the brain that are dominated by myelinated nerve tracts, called white matter, the oligodendrocytes responsible for myelination have a distinctive appearance (Fig. 11-13A). Such an oligodendrocyte has 15 to 30 processes, each of which connects a myelin sheath to the oligodendrocyte's cell body. Each myelin sheath, which is up to 250 µm wide, wraps many times around the long axis of one axon. The small exposed area of axon between adjacent myelin sheaths is called the node of Ranvier (see pp. 200–201). In gray matter, oligodendrocytes do not produce myelin and exist as perineuronal satellite cells.


FIGURE 11-13 Myelination of axons by oligodendrocytes and Schwann cells.

During the myelination process, the leading edge of one of the processes of the oligodendrocyte cytoplasm wraps around the axon many times (see Fig. 11-13A, upper axon). The cytoplasm is then squeezed out of the many cell layers surrounding the axon in a process called compaction. This process creates layer upon layer of tightly compressed membranes that is called myelin. The myelin sheaths remain continuous with the parent glial cells, which nourish them.

In the PNS, a single Schwann cell provides a single myelin segment to a single axon of a myelinated nerve (see Fig. 11-13B). This situation stands in contrast to that in the CNS, where one oligodendrocyte myelinates many axons. The process of myelination that occurs in the PNS is analogous to that outlined for oligodendrocytes. Axons of unmyelinated nerves are also associated with Schwann cells. In this case, the axons indent the surface of the Schwann cell and are completely surrounded by Schwann cell cytoplasm (Fig. 11-14).


FIGURE 11-14 Ensheathed versus myelinated axons. A, Ensheathed axons. This transmission electron micrograph shows a Schwann cell surrounding several unmyelinated peripheral axons, some of which are marked with an asterisk. The arrows point to the basal lamina. The arrowhead points to collagen fibrils. B, Myelinated axons. This transmission electron micrograph shows a Schwann cell (nucleus on right side of picture) surrounding a peripheral axon with several layers of myelin. The lower asterisk shows the beginning of the spiraling myelin sheath, whereas the upper asterisk indicates the termination of the spiral and a small region of noncompacted cytosol. The final magnification is ~14,000 in both panels. (Reproduced from Bunge RP, Fernandez-Valle C: In Kettemann H, Ransom RR [eds]: Neuroglia. New York, Oxford University Press, 1995, pp 44–57. Courtesy of Mary Bartlett Bunge.)

Myelin has a biochemical composition different from that of the oligodendrocyte or Schwann cell plasma membrane from which it arose. Although PNS myelin and CNS myelin look similar, some of the constituent proteins are different (Table 11-4). For example, proteolipid protein is the most common protein in CNS myelin (~50% of total protein) but is absent in PNS myelin. Conversely, P0 is found almost exclusively in PNS myelin.

TABLE 11-4

Proteins in Myelin




























CNP, cyclic nucleotide phosphodiesterase; MAG, myelin-associated glycoprotein; MBP, myelin basic protein; MOG, myelin/oligodendrocyte glycoprotein; PLP, proteolipid protein; PMP22, peripheral myelin protein 22.

Myelination greatly enhances conduction of the action potential down the axon because it allows the regenerative electrical event to skip from one node to the next rather than gradually spreading down the whole extent of the axon. This process is called saltatory conduction (see pp. 200–201). Besides being responsible for CNS myelin, oligodendrocytes play another key role in saltatory conduction: they induce the clustering of Na+ channels at the nodes (see Fig. 12-5C), which is essential for saltatory conduction.

It is well known that severed axons in the PNS can regenerate with restoration of lost function. Regrowth of these damaged axons is coordinated by the Schwann cells in the distal portion of the cut nerve. Severed axons in the CNS do not show functional regrowth, in part because of the growth-retarding nature of myelin-associated glycoproteins (see pp. 267–268).

Oligodendrocytes are involved in pH regulation and iron metabolism in the brain

Oligodendrocytes and myelin contain most of the enzyme carbonic anhydrase within the brain. The appearance of this enzyme during development closely parallels the maturation of these cells and the formation of myelin. Carbonic anhydrase rapidly catalyzes the reversible hydration of CO2 and may thus allow the image buffer system to be maximally effective in dissipating pH gradients in the brain. The pH regulation in the brain is important because it influences neuronal excitability. The classic example of the brain's sensitivity to pH is the reduced seizure threshold caused by the respiratory alkalosis secondary to hyperventilation (see p. 634).

Oligodendrocytes are the cells in the brain most involved with iron metabolism. They contain the iron storage protein ferritin and the iron transport protein transferrin. Iron is necessary as a cofactor for certain enzymes and may catalyze the formation of free radicals (see pp. 1238–1239) under pathological circumstances, such as disruption of blood flow to the brain.

Oligodendrocytes, like astrocytes, have a wide variety of neurotransmitter receptors. Unmyelinated axons can release glutamate when they conduct action potentials, and in principle, this glutamate could signal nearby oligodendrocytes. Ischemia readily injures oligodendrocytes, in part by releasing toxic levels of glutamate. Even white matter, therefore, can suffer excitotoxicity.

Microglial cells are the macrophages of the CNS

Microglial cells are of mesodermal origin and derive from cells related to the monocyte-macrophage lineage. Microglia represent ~20% of the total glial cells within the mature CNS. These cells are rapidly activated by injury to the brain, which causes them to proliferate, to change shape, and to become phagocytic (Fig. 11-15). When activated, they are capable of releasing substances that are toxic to neurons, including free radicals and nitric oxide. It is believed that microglia are involved in most brain diseases, not as initiators but as highly reactive cells that shape the brain's response to any insult.


FIGURE 11-15 Microglial cells. Resting microglial cells become activated by injury to the brain, which causes them to proliferate and to become phagocytic.

Microglia are also the most effective antigen-presenting cells within the brain. Activated T lymphocytes are able to breech the BBB and enter the brain. To become mediators of tissue-specific disease or to destroy an invading infectious agent, T lymphocytes must recognize specific antigenic targets. Such recognition is accomplished through the process of antigen presentation, which is a function of the microglia.