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Glia Form the Insulating Sheaths for Axons
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A major function of oligodendrocytes and Schwann cells is to provide the insulating material that allows rapid conduction of electrical signals along the axon. These cells produce thin sheets of myelin that wrap concentrically, many times, around the axon. Central nervous system myelin, produced by oligodendrocytes, is similar, but not identical to peripheral nervous system myelin, produced by Schwann cells.
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Both types of glia produce myelin only for segments of axons. This is because the axon is not continuously wrapped in myelin, a feature that facilitates propagation of action potentials (see Chapter 6). One Schwann cell produces a single myelin sheath for one segment of one axon, whereas one oligodendrocyte produces myelin sheaths for segments of as many as 30 axons (Figure 4–13).
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The number of layers of myelin on an axon is proportional to the diameter of the axon—larger axons have thicker sheaths. Axons with very small diameters are not myelinated; nonmyelinated axons conduct action potentials much more slowly than do myelinated axons because of their smaller diameter and lack of myelin insulation (see Chapter 6).
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The regular lamellar structure and biochemical composition of the sheath are consequences of how myelin is formed from the glial plasma membrane. In the development of the peripheral nervous system, before myelination takes place, the axon lies within a trough formed by Schwann cells. Schwann cells line up along the axon at regular intervals that become the myelinated segments of axon. The external membrane of each Schwann cell surrounds the axon to form a double membrane structure called the mesaxon, which elongates and spirals around the axon in concentric layers (Figure 4–13C). As the axon is ensheathed, the cytoplasm of the Schwann cell is squeezed out to form a compact lamellar structure.
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The regularly spaced segments of myelin sheath are separated by unmyelinated gaps, called nodes of Ranvier, where the plasma membrane of the axon is exposed to the extracellular space for approximately 1 μm (Figure 4–14). This arrangement greatly increases the speed at which nerve impulses are conducted (up to 100 m/s in humans) because the signal jumps from one node to the next, a mechanism called saltatory conduction (see Chapter 6). Nodes are easily excited because they have a low threshold. In the axon membrane at the nodes the density of Na+ channels, which generate the action potential, is approximately 50 times greater than in myelin-sheathed regions of membrane. Several cell adhesion molecules in the paranodal regions keep the myelin boundaries stable.
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In the human femoral nerve the primary sensory axon is approximately 0.5 m long and the internodal distance is 1 to 1.5 mm; thus approximately 300 to 500 nodes of Ranvier occur along a primary afferent fiber between the thigh muscle and the cell body in the dorsal root ganglion. Because each internodal segment is formed by a single Schwann cell, as many as 500 Schwann cells participate in the myelination of each peripheral sensory axon.
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Myelin has bimolecular layers of lipid interspersed between protein layers. Its composition is similar to that of the plasmalemma, consisting of 70% lipid and 30% protein with high concentrations of cholesterol and phospholipid. In the central nervous system myelin has two major proteins: myelin basic protein, a small, positively charged protein that is situated on the cytoplasmic surface of compact myelin, and proteolipid protein, a hydrophobic integral membrane protein. Presumably, both provide structural stability for the sheath. Both have also been implicated as important autoantigens against which the immune system can react to produce the demyelinating disease, multiple sclerosis. In the peripheral nervous system myelin contains a major protein, P0,, as well as the hydrophobic protein PMP22. Autoimmune reactions to these proteins produce a demyelinating peripheral neuropathy, the Guillain-Barré syndrome. Mutations in myelin protein genes also cause a variety of demyelinating diseases in both peripheral and central axons (Box 4–3). Demyelination slows down, or even stops, conduction of the action potential in an affected axon, because it allows electrical current to leak out of the axonal membrane. Thus, demyelinating diseases have devastating effects on neuronal circuits in the brain, spinal cord, and peripheral nervous system.
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Box 4–3 Defects in Myelin Proteins Disrupt Conduction of Nerve Signals
Because in myelinated axons normal conduction of the nerve impulse depends on the insulating properties of the myelin sheath defective myelin can result in severe disturbances of motor and sensory function.
Many diseases that affect myelin, including some animal models of demyelinating disease, have a genetic basis. The shiverer (or shi) mutant mice have tremors and frequent convulsions and tend to die young. In these mice the myelination of axons in the central nervous system is greatly deficient and the myelination that does occur is abnormal.
The mutation that causes this disease is a deletion of five of the six exons of the gene for myelin basic protein, which in the mouse is located on chromosome 18. The mutation is recessive; a mouse develops the disease only if it has inherited the defective gene from both parents. Shiverer mice that inherit both defective genes have only approximately 10% of the myelin basic protein found in normal mice.
When the wild-type gene is injected into fertilized eggs of the shiverer mutant with the aim of rescuing the mutant, the resulting transgenic mice express the wild-type gene but produce only 20% of the normal amounts of MBPs. Nevertheless, myelination of central neurons in the transgenic mice is much improved. Although they still have occasional tremors, the transgenic mice do not have convulsions and have a normal life span (Figure 4–15).
In both the central and peripheral nervous systems myelin contains a protein termed myelin-associated glycoprotein (MAG). MAG belongs to the immunoglobulin superfamily that includes several important cell surface proteins thought to be involved in cell-to-cell recognition, eg, the major histocompatibility complex of antigens, T-cell surface antigens, and the neural cell adhesion molecule (NCAM).
MAG is expressed by Schwann cells early during production of myelin and eventually becomes a component of mature (compact) myelin. Its early expression, subcellular location, and structural similarity to other surface recognition proteins suggest that it is an adhesion molecule important for the initiation of the myelination process. Two isoforms of MAG are produced from a single gene through alternative RNA splicing.
More than half of the protein in myelin in central axons is the proteolipid protein (PLP), which has five membrane-spanning domains. Proteolipids differ from lipoproteins in that they are insoluble in water. Proteolipids are soluble only in organic solvents because they contain long chains of fatty acids that are covalently linked to amino acid residues throughout the proteolipid molecule. In contrast, lipoproteins are noncovalent complexes of proteins with lipids and often serve as soluble carriers of the lipid moiety in the blood.
Many mutations of PLP are known in humans as well as in other mammals, eg, the jimpy mouse. One example is Pelizaeus-Merzbacher disease, a heterogeneous X-linked disease in humans. Almost all PLP mutations occur in a membrane-spanning domain of the molecule. Mutant animals have reduced amounts of (mutated) PLP, hypomyelination, and degeneration and death of oligodendrocytes. These observations suggest that PLP is involved in the compaction of myelin.
The major protein in mature peripheral myelin, myelin protein zero (MPZ or P0), spans the plasmalemma of the Schwann cell. It has a basic intracellular domain and, like MAG, is a member of the immunoglobulin superfamily. The glycosylated extracellular part of the protein, which contains the immunoglobulin domain, functions as a homophilic adhesion protein during myelin ensheathing by interacting with identical domains on the surface of the apposed membrane. Genetically engineered mice in which the function of P0 has been eliminated have poor motor coordination, tremors, and occasional convulsions.
Observation of trembler mouse mutants led to the identification of peripheral myelin protein 22 (PMP22). This Schwann cell protein spans the membrane four times and is normally present in compact myelin. PMP22 is altered by a single amino acid in the mutants. A similar protein is found in humans, encoded by a gene on chromosome 17.
Mutations of the PMP22 gene on chromosome 17 produce several hereditary peripheral neuropathies, while a duplication of this gene causes one form of Charcot-Marie-Tooth disease (Figure 4–16). Charcot-Marie-Tooth disease, the most common inherited peripheral neuropathy, and is characterized by progressive muscle weakness, greatly decreased conduction in peripheral nerves, and cycles of demyeli nation and remyelination. Because both duplicated genes are active, the disease results from increased production of PMP22 (a two- to three-fold increase in gene dosage). Mutations in a number of genes expressed by Schwann cells can produce inherited peripheral neuropathies.
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Astrocytes Support Synaptic Signaling
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Astrocytes are star-shaped glia found in all areas of the brain; indeed, they constitute nearly half the number of brain cells. They play important roles in nourishing neurons and in regulating the concentrations of ions and neurotransmitters in the extracellular space. But astrocytes and neurons also communicate with each other to modulate synaptic signaling in ways that are still poorly understood.
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Astrocytes have large numbers of thin processes that enfold all the blood vessels of the brain, and ensheath synapses or groups of synapses. By their intimate physical association with synapses, often closer than 1 μm, astrocytes are positioned to regulate extracellular concentrations of ions, neurotransmitters, and other molecules (Figure 4–17).
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How do astrocytes regulate axonal conduction and synaptic activity? The first recognized physiological role was that of K+ buffering. When neurons fire action potentials they release K+ ions into the extracellular space. Because astrocytes have high concentrations of K+ channels in their membranes, they can act as spatial buffers: They take up K+ at sites of neuronal activity, mainly synapses, and release it at distant contacts with blood vessels. Astrocytes can also accumulate K+ locally within their cytoplasmic processes along with Cl– ions and water. Unfortunately, accumulation of ions and water in astrocytes can contribute to severe brain swelling after head injury.
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Astrocytes also regulate neurotransmitter concentrations in the brain. For example, high-affinity transporters located in the astrocyte's plasma membrane rapidly clear the neurotransmitter glutamate from the synaptic cleft (Figure 4–17C). Once within the glial cell, glutamate is converted to glutamine by the enzyme glutamine synthetase. Glutamine is then transferred to neurons, where it serves as an immediate precursor of glutamate (see Chapter 13). Interference with these uptake mechanisms results in high concentrations of extracellular glutamate that can lead to the death of neurons, a process termed excitotoxicity. Astrocytes also degrade dopamine, norepinephrine, epinephrine, and serotonin.
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Astrocytes sense when neurons are active because they are depolarized by the K+ released by neurons and have neurotransmitter receptors similar to those of neurons. For example, Bergmann glia in the cerebellum express glutamate receptors. Thus, the glutamate released at cerebellar synapses affects not only postsynaptic neurons but also astrocytes near the synapse. The binding of these ligands to glial receptors increases the intracellular free Ca2+ concentration, which has several important consequences. The processes of one astrocyte connect to those of neighboring astrocytes through gap junctions, allowing transfer of ions and small molecules between many cells. An increase in free Ca2+ within one astrocyte increases Ca2+ concentrations in adjacent astrocytes. This spread of Ca2+ through the astrocyte network occurs over hundreds of micrometers. It is likely that this Ca2+ wave modulates nearby neuronal activity by triggering the release of nutrients and regulating blood flow. An increase in Ca2+ in astrocytes leads to the secretion of signals that enhance synaptic function, but the specific molecular components of these signals are not understood.
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Astrocytes also are important for the development of synapses. They prepare the surface of the neuron for synapse formation and stabilize newly formed synapses. For example, astrocytes secrete substances called thrombospondins that promote the formation of new synapses. In pathological states, such as chromatolysis produced by axonal damage, astrocytes and presynaptic terminals temporarily retract from the damaged postsynaptic cell bodies. Astrocytes release neurotrophic and gliotrophic factors that promote the development and survival of neurons and oligodendrocytes. Astrocytes also protect other cells from the effects of oxidative stress. For example, the gluta thione peroxidase in astrocytes detoxifies toxic oxygen free radicals released during hypoxia, inflammation, and neuronal degeneration.
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Finally, astrocytes ensheath small arterioles and capillaries throughout the brain, forming contacts between the ends of astrocyte processes and the basal lamina around endothelial cells. The central nervous system is sequestered from the general circulation so that macromolecules in the blood do not passively enter the brain and spinal cord (the "blood-brain barrier"). The barrier is largely the result of tight junctions between endothelial cells and cerebral capillaries, a feature not shared by capillaries in other parts of the body (see Appendix D). Nevertheless, endothelial cells have a number of transport properties that allow some molecules to pass through them into the nervous system. Because of the intimate astrocyte–blood vessel contacts, the transported molecules, such as glucose, come into contact with and can be taken up by astrocyte end-feet.
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Choroid Plexus and Ependymal Cells Produce Cerebrospinal Fluid
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Cells of the ependyma and choroid plexus are derived from immature neuroepithelium. The ependyma, a single layer of ciliated cuboidal cells, lines all the ventricles of the brain, helping to move cerebrospinal fluid through the ventricular system (Figure 4–18A). At several places in the lateral and fourth ventricles the ependyma is continuous with cells of the choroid plexus, which covers thin blood vessels that project into the ventricles (Figure 4–18B). These choroid plexus epithelial cells filter plasma from the blood and secrete this ultrafiltrate as cerebrospinal fluid. Cerebrospinal fluid production and the properties of choroid plexus cells are considered in detail in Appendix D.
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Microglia in the Brain Are Derived from Bone Marrow
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Unlike neurons, astrocytes, and oligodendrocytes, microglia do not belong to the neuroectodermal lineage. Instead they derive from bone marrow. Entering the central nervous system early in development, they reside in all regions of the brain throughout life (Figure 4–19). Their functions are not well understood, although they probably play an important role in immunological surveillance in the CNS, poised to react to foreign invaders.
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Of all of the cells in the central nervous system, microglia are the best at processing and presenting antigens to lymphocytes and secreting cytokines and chemokines during inflammation. Thus they serve to bring lymphocytes, neutrophils, and monocytes into the central nervous system and expand the lymphocyte population, important immunological activities in infection, stroke, and immune-mediated demyelinating disease. Microglia can also become macrophages, clearing debris after infarcts (strokes) or other degenerative neurological disorders.