Cohen and pfaff protein kinase Il, which is also implicated in long term processes. Calcium levels may be regulated by the membranous spine apparatus(Fig. 12), because Ca+-ATPase, the IP receptor, and calcium are loca ized there 5. GLIAL CELLS Neuronal form is largely a function of the internal cytoskeletal framework. However, neurons are also supported externally by a second type of cell in the nervous system, the glial cell. Glial cells are present in the central and peripheral nervous systems. Glia fill in all spaces not occupied by neurons and blood vessels rrounding and investing virtually all exposed sur- Fig 12 Electron micrograph of a dendritic spine of the soma- faces in the central nervous system and axons in the tosensory cortex of an adult rat. a presynaptic terminal (P contacts a dendritic spine that emanates from a dendrite(D). peripheral nervous system. Glial cells vary in mor- The dendritic spine is characterized by a head(asterisk)and phology, and their function is not restricted to short neck(arrows)region. A membranous spine apparatus mechanical support. In the central nervous system, SA)is seen in the head region. Mitochondria(M)are seen in glia are subdivided into four main types: astrocyte the dendrite. (Image courtesy of Chiye Aoki, Center for microglia, oligodendrocytes, and ependymal cells. In Neural Science, New York University. the peripheral nervous system, Schwann cells function in a manner similar to that of oligodendrocytes, form- The existence of dendritic spines greatly increases ing insulating myelin sheaths around axons that facil he surface area of a neuron and thus allows for a itate conduction greater number of potential interactions with other neurons. In addition, research in recent years has 5.1. Glia Play a variety of roles in the evealed that the spines themselves can change Nervous System shape according to changing physiologic conditions, 5.1.1. AsTRoGLIA such as altered hormone levels and environmental Astrocytes are stellate-shaped cells with a multitude stress. One way in which synaptic inputs can change of processes that radiate from the cell(Fig. 13A) spine morphology is that the size of a spine is corre- These processes are supported internally by a glial lated with the numbers of docked vesicles in the pre- specific intermediate filament protein, glial fibrillary synaptic ending, thus suggesting the size of the spine acidic protein. Protoplasmic astrocytes are more head will be a monotonically increasing function of abundant in gray matter and have relatively short the amount of current entering the neuron through branching cytoplasmic processes; fibrous astrocytes, the spine. The cytoskeletal network comprising the on the other hand, are usually seen in white matter interior of the spine includes actin and myosin. These and display fewer processes and less branching. Some proteins may play a role in spine contractility, which astrocytic processes may terminate as swellings called may lead to changes in the shape or number of spines. end-feet on neurons and blood vessels(Fig. 13A, B) Some authors believe that abnormalities of dendritic Astrocytes may accumulate extracellular potassium spine morphology and chemistry could result in aber- resulting from the repeated firing of neurons.The rant synaptic signaling accompanied by neurologic potassium may then be released by astrocytic end disorders such as mental retardation feet onto blood vessels to increase their diameter. In Dendritic spines may function as calcium isolation this way, increased neuronal activity may be sup- compartments that decouple calcium changes in the ported by a concomitant increase in blood flow and spine head from those in the dendritic shaft and from oxygen consumption neighboring spines. This possibility has important In nd-feet contribute to implications for explaining LTP. LTP may be synapse formation of the blood-brain barrier(Fig. 13B).Here, specific; its expression is a function of activation of the end-feet are in close proximity to specialized calcium-dependent processes at the synapse, such as capillary endothelial cells and their endothelial basal the activity of the Ca2+ and calmodulin-dependent lamina. There are no tight junctions between glia cells
The existence of dendritic spines greatly increases the surface area of a neuron and thus allows for a greater number of potential interactions with other neurons. In addition, research in recent years has revealed that the spines themselves can change shape according to changing physiologic conditions, such as altered hormone levels and environmental stress. One way in which synaptic inputs can change spine morphology is that the size of a spine is correlated with the numbers of docked vesicles in the presynaptic ending, thus suggesting the size of the spine head will be a monotonically increasing function of the amount of current entering the neuron through the spine. The cytoskeletal network comprising the interior of the spine includes actin and myosin. These proteins may play a role in spine contractility, which may lead to changes in the shape or number of spines. Some authors believe that abnormalities of dendritic spine morphology and chemistry could result in aberrant synaptic signaling accompanied by neurologic disorders such as mental retardation. Dendritic spines may function as calcium isolation compartments that decouple calcium changes in the spine head from those in the dendritic shaft and from neighboring spines. This possibility has important implications for explaining LTP. LTP may be synapse specific; its expression is a function of activation of calcium-dependent processes at the synapse, such as the activity of the Ca2+ and calmodulin-dependent protein kinase II, which is also implicated in longterm processes. Calcium levels may be regulated by the membranous spine apparatus (Fig. 12), because Ca2+-ATPase, the IP receptor, and calcium are localized there. 5. GLIAL CELLS Neuronal form is largely a function of the internal cytoskeletal framework. However, neurons are also supported externally by a second type of cell in the nervous system, the glial cell. Glial cells are present in the central and peripheral nervous systems. Glia fill in all spaces not occupied by neurons and blood vessels, surrounding and investing virtually all exposed surfaces in the central nervous system and axons in the peripheral nervous system. Glial cells vary in morphology, and their function is not restricted to mechanical support. In the central nervous system, glia are subdivided into four main types: astrocytes, microglia, oligodendrocytes, and ependymal cells. In the peripheral nervous system, Schwann cellsfunction in a manner similar to that of oligodendrocytes, forming insulating myelin sheaths around axons that facilitate conduction. 5.1. Glia Play a Variety of Roles in the Nervous System 5.1.1. ASTROGLIA Astrocytes are stellate-shaped cells with a multitude of processes that radiate from the cel1 (Fig. 13A). These processes are supported internally by a glialspecific intermediate filament protein, glial fibrillary acidic protein. Protoplasmic astrocytes are more abundant in gray matter and have relatively short, branching cytoplasmic processes; fibrous astrocytes, on the other hand, are usually seen in white matter and display fewer processes and less branching. Some astrocytic processes may terminate as swellings called end-feet on neurons and blood vessels (Fig. 13A, B). Astrocytes may accumulate extracellular potassium resulting from the repeated firing of neurons. The potassium may then be released by astrocytic endfeet onto blood vessels to increase their diameter. In this way, increased neuronal activity may be supported by a concomitant increase in blood flow and oxygen consumption. Importantly, astrocyte end-feet contribute to the formation of the blood-brain barrier (Fig. 13B). Here, the end-feet are in close proximity to specialized capillary endothelial cells and their endothelial basal lamina. There are no tight junctions between glia cells. Fig. 12. Electron micrograph of a dendritic spine of the somatosensory cortex of an adult rat. A presynaptic terminal (PR) contacts a dendritic spine that emanates from a dendrite (D). The dendritic spine is characterized by a head (asterisk) and short neck (arrows) region. A membranous spine apparatus (SA) is seen in the head region. Mitochondria (M) are seen in the dendrite. (Image courtesy of Chiye Aoki, Center for Neural Science, New York University.) 18 Cohen and Pfaff
Chapter 1/Cytology and Organization of Cell Types 19 blood-brain barrier between blood and cerebrospinal fluid. The choroids plexus is a modification of the ependyma, a ciliated cellular lining of the central canal system of the brain and spinal cord Normally, the blood-brain barrier also excludes cells, such as leukocytes, immune mediators, as well as dyes and antibiotics from entering the brain. How- ever the blood-brain barrier can be breached for example, by bacterial components, in several ways One strategy is invasion engineered by the pathogen itself. For example, astroglial dysfunction caused by the bacterium Listeria results in an opening of tight junctions and subsequent penetration by this organ ism. The spirochete Treponema can cross between blood-brain barrier endothelial cells. The two patho- genic microorganisms, Streptococcus pneumoniae and Plasmodium, have specific receptors on endothelial cells that permit transmigration across the barrier The blood- brain barrier is not just a“gate”to prevent entry into the blood, but rather a mode of communication between the nervous and immune systems. The endothelial or epithelial barriers them- selves can secrete cytokines, signaling proteins and peptides, especially important in immune responses Fig 13. Astrocytes from monkey cortex. The light micrograph and also be regulated by cytokines. Some regions of in(A)shows a brain section treated with Cajal's silver stain, the brain, such as the circumventricular organs, have which stains internal fibrous elements black. Two star-shaped leaky vessels and lack a blood-brain barrier; most astrocytes are seen, and the processes emanating from them are epithelial regions of the ependyma(except the cho labeled by asterisks. The astrocyte end-feet(arrows) emerging oid plexus described above) are also leaky.Because of from the indicated processes are in contact with a blood vessel the restrictions on the size and chemical composition (BV). The diagram in(B)shows the end-feet(EF)in intimate contact with a capillary. At the right, in cross-section, the of molecules that are able to cross the blood-brain endothelial cell(EC)of the capillary is seen surrounded by a barrier, drug delivery to the brain is hindered, thereby basal lamina(BL). A tight junction(TJ) is present between presenting a challenge to the development of phar endothelial cells comprising the capillary. There are no tight maceuticals capable of crossing the barrier junctions between astrocyte end-feet. A pericyte(not shown) As stated earlier, glial cells formerly were theoreti urrounds the basal lamina cally assigned modest roles in nervous system func- tion, being thought of primarily as supportive in ways However, the functional integrity of the tight Junc- both mechanical and metabolic. Now. however, it is tions between endothelial cells, which prevent entry of understood that astrocytes can play dynamic roles at solutes and fluid into the brain tissue, appears to some of the most important synapses in the nerve depend upon normal functioning of the astrocyte. system. Philip Haydon has given voice to this fact in Active transport by specific receptor-mediated endo- his concept of the "tripartite synapse"that includes cytosis permits entrance across the capillary wall. not only the classically recognized presynaptic and Some lipid-soluble molecules, such as steroid hor- postsynaptic elements but also an enveloping glial mones,oxygen, and carbon dioxide, can pass through cell. For example, in synapses that use glutamate as the barrier, but other molecules, such as amino acids. the transmitter--glutamate being the oldest and most require specific carrier molecules rapidly signaling excitatory transmitter--the gluta Another blood-brain barrier is associated with the mate released is actively transported into a neighbor choroid plexus epithelium, located within the lateral, ing astrocyte thus limiting its duration of action in the third and fourth ventricles; this is a highly vascular- synapse. In the astrocyte, it is enzymatically trans Tioi epithelium, which produces cerebrospinal fluid. formed into glutamine and then released. The presy- t junctions between epithelial cells constitute the haptic glutamatergic ending actively transports it into
However, the functional integrity of the tight junctions between endothelial cells, which prevent entry of solutes and fluid into the brain tissue, appears to depend upon normal functioning of the astrocyte. Active transport by specific receptor-mediated endocytosis permits entrance across the capillary wall. Some lipid-soluble molecules, such as steroid hormones, oxygen, and carbon dioxide, can pass through the barrier, but other molecules, such as amino acids, require specific carrier molecules. Another blood-brain barrier is associated with the choroid plexus epithelium, located within the lateral, third and fourth ventricles; this is a highly vascularized epithelium, which produces cerebrospinal fluid. Tight junctions between epithelial cells constitute the blood-brain barrier between blood and cerebrospinal fluid. The choroids plexus is a modification of the ependyma, a ciliated cellular lining of the central canal system of the brain and spinal cord. Normally, the blood-brain barrier also excludes cells, such as leukocytes, immune mediators, as well as dyes and antibiotics from entering the brain. However, the blood-brain barrier can be breached, for example, by bacterial components, in several ways. One strategy is invasion engineered by the pathogen itself. For example, astroglial dysfunction caused by the bacterium Listeria results in an opening of tight junctions and subsequent penetration by this organism. The spirochete Treponema can cross between blood-brain barrier endothelial cells. The two pathogenic microorganisms, Streptococcus pneumoniae and Plasmodium, have specific receptors on endothelial cells that permit transmigration across the barrier. The blood-brain barrier is not just a ‘‘gate’’ to prevent entry into the blood, but rather a mode of communication between the nervous and immune systems. The endothelial or epithelial barriers themselves can secrete cytokines, signaling proteins and peptides, especially important in immune responses, and also be regulated by cytokines. Some regions of the brain, such as the circumventricular organs, have leaky vessels and lack a blood-brain barrier; most epithelial regions of the ependyma (except the choroid plexus described above) are also leaky. Because of the restrictions on the size and chemical composition of molecules that are able to cross the blood-brain barrier, drug delivery to the brain is hindered, thereby presenting a challenge to the development of pharmaceuticals capable of crossing the barrier. As stated earlier, glial cells formerly were theoretically assigned modest roles in nervous system function, being thought of primarily as supportive in ways both mechanical and metabolic. Now, however, it is understood that astrocytes can play dynamic roles at some of the most important synapses in the nervous system. Philip Haydon has given voice to this fact in his concept of the ‘‘tripartite synapse’’ that includes not only the classically recognized presynaptic and postsynaptic elements but also an enveloping glial cell. For example, in synapses that use glutamate as the transmitter—glutamate being the oldest and most rapidly signaling excitatory transmitter—the glutamate released is actively transported into a neighboring astrocyte thus limiting its duration of action in the synapse. In the astrocyte, it is enzymatically transformed into glutamine and then released. The presynaptic glutamatergic ending actively transports it into Fig. 13. Astrocytes from monkey cortex. The light micrograph in (A) shows a brain section treated with Cajal’s silver stain, which stains internal fibrous elements black. Two star-shaped astrocytes are seen, and the processes emanating from them are labeled by asterisks. The astrocyte end-feet (arrows) emerging from the indicated processes are in contact with a blood vessel (BV). The diagram in (B) shows the end-feet (EF) in intimate contact with a capillary. At the right, in cross-section, the endothelial cell (EC) of the capillary is seen surrounded by a basal lamina (BL). A tight junction (TJ) is present between endothelial cells comprising the capillary. There are no tight junctions between astrocyte end-feet. A pericyte (not shown) surrounds the basal lamina. Chapter 1 / Cytology and Organization of Cell Types 19
Cohen and pfaff the nerve cell and, using the enzyme glutaminase, lymphocytes, monocytes, and neutrophils, which, in makes more glutamate. Thus, changes in the mor- turn, can also act in defense of the brain Microglia phology and biochemical efficiency of the astrocytes have been implicated in a wide spectrum of diseases in question would have important neuromodulatory including those caused by microorganisms, such consequences. human immunodeficiency virus-associated demen Morphologic analyses indicate that astrocytic pro- tia, cytomegalovirus, herpes simplex virus, cerebral cesses preferentially contact neuronal surfaces over malaria, as well as neuroinflammatory and neurode- those of other glia, despite a ratio of glia to neurons of generative diseases, such as multiple sclerosis, Alzhei at least 10 to 1. Other evidence suggests that associa- mers disease, Parkinsons disease, and Huntington tions between neurons and glia are constantly in flux disease throughout the life of the organism. Glia may pro- Microglia are not the only immune cells in the mote or inhibit the outgrowth of neuronal processes CNS. Mast cells, which are also derived from bone during development by synthesizing and secreting marrow and function in the immune system, occur in various adhesion molecules. In some parts of the the in the healthy and diseased adult brain In experi developing nervous system, such as the cerebellum mental allergic encephalitis, a mouse model of multi and neural tube, radial glial cells form a transient ple sclerosis, mast cells are seen close to plaques. scaffold that guides the migration of immature neu- characteristic of this disease. Mature mast cells have rons to their final destinations. The migrating neu- granules that function as storage for effector mole rons wrap around these pole-shaped cells and crawl cules, including histamine and neuropeptides, and along them. After completion of the trip, the radial enzymes. Upon activation, these cells synthesize and glia disappear and may be transformed into astro- release various molecules, including those involved in cytes. In the central nervous system, astrocytes and immune reactions, such as cytokines; they also take macrophages, called microglia, remove the cellular up molecules and particles, such as bacteria. Interest debris resulting from degenerative processes ingly, mast cell number in the brain is a function of 5.1.2. MICRoGLIA reproductive behavior and endocrine status and therefore, may be involved in neuroimmune function Microglia constitute only a small portion (5%)of number to neurons(e15% of the cell population ) 5.2. Glia Form Myelin Sheaths That Increase the They originate from bone marrow monocyte precur- Speed and Efficiency of Conduction in Axons sor cells and are, therefore, thought to be part of the Oligodendrocytes and Schwann cells form myelin mononuclear phagocyte system. Along with astroglia, sheaths around axons. These sheaths are formed by microglia are part of the immune system of the CNS. the attenuation of the glial cytoplasm to such an They are the smallest of the glial cells. Embryonically, extent that most of the sheath is composed of con- microglia are ameboid and in the adult, resting state centric layers of plasma membrane wrapping around display short processes, branched processes. At sites the axon(Fig. 14 and Fig. 15). In oligodendrocytes, of injury and disease, microglia proliferate, return to several processes extend out from the cell, tapering as their ameboid configuration, and become motile and they encounter an axon, and wrap around a portion actively phagocytic. Cell surface markers central to of its length. One oligodendrocyte can ensheathe immune function, such as the MHC class II mole- many axons, all of different neuronal origins. Indivi- cules, are constitutively expressed on adult, resting dual Schwann cells dedicate themselves to a single microglia. However, when activated, a large number axon. The exposed patch of axon in between adjacent of receptor types are rapidly upregulated, and a num- segments of the myelin sheath is called the node of ber of secretory products, such as cytokines and che- Ranvier(Fig. 14 and Fig. 15). Most of the Naion mokines, are produced that can either defend or channels of the axon are confined to this site. Because damage the diseased brain. Microglial generation of of the lack of channels between the nodes and great free radicals(e.g, reactive oxygen or nitrogen inter- insulating action of the myelin sheath, there is vir- mediates)are also implicated in defense of, as well as tually no current flow across these segments. The damage to, neurons. Other secretory products play a action potential bypasses these stretches of mem- role in blood-brain barrier breakdown, which may brane by jumping from node to node. This type of result in leukocyte infiltration into the nervous sys- rapid propagation is known as saltatory conduction tem and tissue destruction. In addition to these inher- An added advantage is that energy is conserved ent features of microglia, these cells can also recruit fewer ions enter and leave the axon so less energy is
the nerve cell and, using the enzyme glutaminase, makes more glutamate. Thus, changes in the morphology and biochemical efficiency of the astrocytes in question would have important neuromodulatory consequences. Morphologic analyses indicate that astrocytic processes preferentially contact neuronal surfaces over those of other glia, despite a ratio of glia to neurons of at least 10 to 1. Other evidence suggests that associations between neurons and glia are constantly in flux throughout the life of the organism. Glia may promote or inhibit the outgrowth of neuronal processes during development by synthesizing and secreting various adhesion molecules. In some parts of the developing nervous system, such as the cerebellum and neural tube, radial glial cells form a transient scaffold that guides the migration of immature neurons to their final destinations. The migrating neurons wrap around these pole-shaped cells and crawl along them. After completion of the trip, the radial glia disappear and may be transformed into astrocytes. In the central nervous system, astrocytes and macrophages, called microglia, remove the cellular debris resulting from degenerative processes. 5.1.2. MICROGLIA Microglia constitute only a small portion (5%) of the glial cell population but are roughly equivalent in number to neurons (15% of the cell population). They originate from bone marrow monocyte precursor cells and are, therefore, thought to be part of the mononuclear phagocyte system. Along with astroglia, microglia are part of the immune system of the CNS. They are the smallest of the glial cells. Embryonically, microglia are ameboid and in the adult, resting state display short processes, branched processes. At sites of injury and disease, microglia proliferate, return to their ameboid configuration, and become motile and actively phagocytic. Cell surface markers central to immune function, such as the MHC class II molecules, are constitutively expressed on adult, resting microglia. However, when activated, a large number of receptor types are rapidly upregulated, and a number of secretory products, such as cytokines and chemokines, are produced that can either defend or damage the diseased brain. Microglial generation of free radicals (e.g., reactive oxygen or nitrogen intermediates) are also implicated in defense of, as well as damage to, neurons. Other secretory products play a role in blood-brain barrier breakdown, which may result in leukocyte infiltration into the nervous system and tissue destruction. In addition to these inherent features of microglia, these cells can also recruit lymphocytes, monocytes, and neutrophils, which, in turn, can also act in defense of the brain. Microglia have been implicated in a wide spectrum of diseases, including those caused by microorganisms, such as human immunodeficiency virus–associated dementia, cytomegalovirus, herpes simplex virus, cerebral malaria, as well as neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington disease. Microglia are not the only immune cells in the CNS. Mast cells, which are also derived from bone marrow and function in the immune system, occur in the in the healthy and diseased adult brain. In experimental allergic encephalitis, a mouse model of multiple sclerosis, mast cells are seen close to plaques, characteristic of this disease. Mature mast cells have granules that function as storage for effector molecules, including histamine and neuropeptides, and enzymes. Upon activation, these cells synthesize and release various molecules, including those involved in immune reactions, such as cytokines; they also take up molecules and particles, such as bacteria. Interestingly, mast cell number in the brain is a function of reproductive behavior and endocrine status and, therefore, may be involved in neuroimmune function. 5.2. Glia Form Myelin Sheaths That Increase the Speed and Efficiency of Conduction in Axons Oligodendrocytes and Schwann cells form myelin sheaths around axons. These sheaths are formed by the attenuation of the glial cytoplasm to such an extent that most of the sheath is composed of concentric layers of plasma membrane wrapping around the axon (Fig. 14 and Fig. 15). In oligodendrocytes, several processes extend out from the cell, tapering as they encounter an axon, and wrap around a portion of its length. One oligodendrocyte can ensheathe many axons, all of different neuronal origins. Individual Schwann cells dedicate themselves to a single axon. The exposed patch of axon in between adjacent segments of the myelin sheath is called the node of Ranvier (Fig. 14 and Fig. 15). Most of the Na+ ion channels of the axon are confined to this site. Because of the lack of channels between the nodes and great insulating action of the myelin sheath, there is virtually no current flow across these segments. The action potential bypasses these stretches of membrane by jumping from node to node. This type of rapid propagation is known as saltatory conduction. An added advantage is that energy is conserved; fewer ions enter and leave the axon so less energy is 20 Cohen and Pfaff
Chapter 1/Cytology and Organization of Cell Types M NR 复复 Axon . ax SC Fig. 14. Diagrams of myelinated axons of the peripheral and central nervous systems. (A)In the peripheral axon, several M Schwann cells wrap their plasma membrane concentrically around a single axon. The stretch of axonal membrane, called the axolemma, between adjacent Schwann cells is known as the node of Ranvier. (B)In the central axon, several glial processes emerge from one oligodendrocyte and ensheathe several axons of different origins expended in returning the membrane to its origina polarized state by active transport mechanisms Fig. 15. Electron micrographs of myelin sheaths of axons. (A)A longitudinal section through the axon(ax) shows that 5.3. Neuropathologies Related to Myelin the sheath is interrupted at regular intervals, called nodes of Ranvier(nr), where portions of the axonal membrane, called There are many neuropathologies related to mye- the axolemma(arrow), are exposed. Sodium ion channels are lin that have various etiologies; some are acquired concentrated in the axolemma at the nodes. (B)A cross and others are inherited. An example of the former tion of the axon (ax) shows the surrounding myelin sheath is multiple sclerosis, an inflammatory, demyelinat- ( and Schwann cell sc) cytoplasm. mages courtesy of ing disease, characterized by muscle weakness and for Microscopy and Imaging Research.) subsequent problems, such as declining mobility, extreme fatigue, and impaired coordination and speech. An animal model of multiple sclerosis that the mBP present in wild-type mice. Injection of the exploits the antigenicity of myelin proteins and sub- wild-type gene into the fertilized eggs of the shiverer sequent robust immune response is experimental mouse by transgenic technology rescues the mutant allergic encephalitis. One class of these proteins, which then can express 20% of the normal levels of myelin basic proteins(MBP), plays a key role in MBP; however, apart from some tremors, these myelin compaction. Related proteins are generated mice do not have convulsions and live a normal from a single MBP gene by alternative RNA spli- life span cing. Another animal model of this disease is the In Guillain-Barre syndrome(acute inflammatory shiverer mutant mouse. These mice also exhibit demyelinating polyradiculoneuropathy ), an autoim demyelination, display tremors, convulsions, and mune disease of the peripheral nervous system, die young. They lack five of the six exons for the there is a large accumulation of lymphocytes. myelin basic protein gene and exhibit only 10% of macrophages, and plasma cells around nerve fibers
expended in returning the membrane to its original polarized state by active transport mechanisms. 5.3. Neuropathologies Related to Myelin There are many neuropathologies related to myelin that have various etiologies; some are acquired and others are inherited. An example of the former is multiple sclerosis, an inflammatory, demyelinating disease, characterized by muscle weakness and subsequent problems, such as declining mobility, extreme fatigue, and impaired coordination and speech. An animal model of multiple sclerosis that exploits the antigenicity of myelin proteins and subsequent robust immune response is experimental allergic encephalitis. One class of these proteins, myelin basic proteins (MBP), plays a key role in myelin compaction. Related proteins are generated from a single MBP gene by alternative RNA splicing. Another animal model of this disease is the shiverer mutant mouse. These mice also exhibit demyelination, display tremors, convulsions, and die young. They lack five of the six exons for the myelin basic protein gene and exhibit only 10% of the MBP present in wild-type mice. Injection of the wild-type gene into the fertilized eggs of the shiverer mouse by transgenic technology rescues the mutant, which then can express 20% of the normal levels of MBP; however, apart from some tremors, these mice do not have convulsions and live a normal life span. In Guillain-Barre´ syndrome (acute inflammatory demyelinating polyradiculoneuropathy), an autoimmune disease of the peripheral nervous system, there is a large accumulation of lymphocytes, macrophages, and plasma cells around nerve fibers Fig. 14. Diagrams of myelinated axons of the peripheral and central nervous systems. (A) In the peripheral axon, several Schwann cells wrap their plasma membrane concentrically around a single axon. The stretch of axonal membrane, called the axolemma, between adjacent Schwann cells is known as the node of Ranvier. (B) In the central axon, several glial processes emerge from one oligodendrocyte and ensheathe several axons of different origins. Fig. 15. Electron micrographs of myelin sheaths of axons. (A) A longitudinal section through the axon (ax) shows that the sheath is interrupted at regular intervals, called nodes of Ranvier (NR), where portions of the axonal membrane, called the axolemma (arrow), are exposed. Sodium ion channels are concentrated in the axolemma at the nodes. (B) A cross section of the axon (ax) shows the surrounding myelin sheath (M) and Schwann cell (SC) cytoplasm. (Images courtesy of Thomas Deerinck and Mark Ellisman, the National Center for Microscopy and Imaging Research.) Chapter 1 / Cytology and Organization of Cell Types 21
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