Principles of Neural Science, Fifth Edition

4: The Cells of the Nervous System

Introduction

Neurons and Glia Share Many Structural and Molecular Characteristics
The Cytoskeleton Determines Cell Shape
Protein Particles and Organelles Are Actively Transported Along the Axon and Dendrites
- Fast Axonal Transport Carries Membranous Organelles
- Slow Axonal Transport Carries Cytosolic Proteins and Elements of the Cytoskeleton
Proteins Are Made in Neurons as in Other Secretory Cells
- Secretory and Membrane Proteins Are Synthesized and Modified in the Endoplasmic Reticulum
- Secretory Proteins Are Modified in the Golgi Complex
Surface Membrane and Extracellular Substances Are Recycled in the Cell
Glial Cells Play Diverse Roles in Neural Function
- Glia Form the Insulating Sheaths for Axons
- Astrocytes Support Synaptic Signaling
- Choroid Plexus and Ependymal Cells Produce Cerebrospinal Fluid
- Microglia in the Brain Are Derived from Bone Marrow
An Overall View

Neurons and glia—the cells from which the nervous system is assembled—share many characteristics with cells in general. However, neurons are specially endowed with the ability to communicate precisely and rapidly with other cells at distant sites in the body. Two features give neurons this ability.

First, they have a high degree of morphological and functional asymmetry: Neurons have receptive dendrites at one end and a transmitting axon at the other. This arrangement is the structural basis for unidirectional neuronal signaling.

Second, neurons are both electrically and chemically excitable. The cell membrane of neurons contains specialized proteins—ion channels and receptors—that facilitate the flow of specific inorganic ions, thereby redistributing charge and creating electrical currents that alter the voltage across the membrane. These changes in charge can produce a wave of depolarization in the form of action potentials along the axon, the usual way a signal travels within the neuron. Glia are less excitable, but their membranes contain transporter proteins that facilitate the uptake of ions as well as proteins that remove neurotransmitter molecules from the extracellular space, thus regulating neuronal function.

There are about 100 distinct types of neurons. This cytological diversity is also apparent at the molecular level. Although neurons all inherit the same complement of genes, each expresses a restricted set and thus produces only certain molecules—enzymes, structural proteins, membrane constituents, and secretory products—and not others. In large part this expression depends on the cell's developmental history. In essence each cell is the set of molecules that it makes.

Neurons and Glia Share Many Structural and Molecular Characteristics

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Neurons and glia develop from common neuroepithelial cells of the embryonic nervous system and thus share many structural and molecular characteristics (Figure 4–1). The boundaries of these cells are defined by the cell membrane or plasmalemma, which has the asymmetric bilayer structure of all biological membranes and provides a hydrophobic barrier impermeable to most water-soluble substances. Cytoplasm has two main components: cytosol and membranous organelles.

Figure 4–1

The structure of a neuron.

The cell body and nucleus of a spinal motor neuron are surrounded by a double- layered membrane, the nuclear envelope, which is continuous with the endoplasmic reticulum. The space between the two membrane layers that constitutes the nuclear envelope is continuous with the lumen of the endoplasmic reticulum. Dendrites emerge from the basal aspect of the neuron, the axon from the apical aspect. (Adapted, with permission, from Williams et al. 1989.)

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Cytosol is the aqueous phase of cytoplasm. In this phase only a few proteins are actually free in solution. With the exception of some enzymes that catalyze metabolic reactions, most proteins are organized into functional complexes. A recent subdiscipline called proteomics has determined that these complexes can consist of many distinct proteins, none of which are covalently linked to another. For example, the cytoplasmic tail of the N-methyl-D-aspartate (NMDA)-type glutamate receptor, a membrane-associated protein that mediates excitatory synaptic transmission in the central nervous system, is anchored in a large complex of more than 100 scaffold proteins and protein-modifying enzymes. (Many cytosolic proteins involved in second-messenger signaling, discussed in later chapters, are embedded in the cytoskeletal matrix immediately underneath the plasmalemma.) Ribosomes, the organelle on which messenger RNA (mRNA) molecules are translated, are made up of several protein subunits. Proteasomes, large multienzyme organelles that degrade ubiquitinated proteins (a process described later in this chapter), are also present throughout the cytosol of neurons and glia.

Membranous organelles, the second main component of cytoplasm, include mitochondria and peroxisomes as well as a complex system of tubules, vesicles, and cisternae called the vacuolar apparatus. Mitochondria and peroxisomes process molecular oxygen. Mitochondria generate adenosine triphosphate (ATP), the major molecule by which cellular energy is transferred or spent, whereas peroxisomes prevent accumulation of the strong oxidizing agent hydrogen peroxide. Thought to be derived from symbiotic organisms that invaded eukaryotic cells early in evolution, these two organelles are not functionally continuous with the vacuolar apparatus.

The vacuolar apparatus includes the rough endoplasmic reticulum, the smooth endoplasmic reticulum, the Golgi complex, secretory vesicles, endosomes, lysosomes, and a multiplicity of transport vesicles that interconnect these various compartments (Figure 4–2). Their lumen corresponds topologically to the outside of the cell; consequently, the inner leaflet of their lipid bilayer corresponds to the outer leaflet of the plasmalemma.

Figure 4–2

Organelles of the neuron.

Electron micrographs show cytoplasm in four different regions of the neuron. (Adapted, with permission, from Peters et al. 1991.)

A. A dendrite emerges from a pyramidal neuron's cell body, which includes the endoplasmic reticulum (ER) above the nucleus (N) and a portion of the Golgi complex (G) nearby. Some Golgi cisternae have entered the dendrite, as have mitochondria (Mit), lysosomes (Ly), and ribosomes (R). Microtubules (Mt) are prominent cytoskeletal filaments in the cytosol. Axon terminals (AT) making contact with the dendrite are seen at the top and right.

B. Some components of a spinal motor neuron that participate in the synthesis of macromolecules. The nucleus (N), containing masses of chromatin (Ch), is bounded by the nuclear envelope, which contains many nuclear pores (arrows). The mRNA leaves the nucleus through these pores and attaches to ribosomes that either remain free in the cytoplasm or attach to the membranes of the endoplasmic reticulum to form the rough endoplasmic reticulum (RER). Regulatory proteins synthesized in the cytoplasm are imported into the nucleus through the pores. Several parts of the Golgi apparatus (G) are seen, as are lysosomes (Ly) and mitochondria (Mit).

C–D. Micrographs of a dorsal root ganglion cell (C) and a motor neuron (D) show the organelles in the cell body that are chiefly responsible for synthesis and processing of proteins. The mRNA enters the cytoplasm through the nuclear envelope and is translated into proteins. Free polysomes, strings of ribosomes attached to a single mRNA, generate cytosolic proteins and proteins to be imported into mitochondria (Mit) and peroxisomes. Proteins destined for the endoplasmic reticulum are formed after the polysomes attach to the membrane of the endoplasmic reticulum (ER). The particular region of the motor neuron shown here also includes membranes of the Golgi apparatus (G), in which membrane and secretory proteins are further processed. Some of the newly synthesized proteins leave the Golgi apparatus in vesicles that move down the axon to synapses; other membrane proteins are incorporated into lysosomes (Ly) and other membranous organelles. The microtubules (M) and neurofilaments (Nf) are components of the cytoskeleton.

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The major subcompartments of this system are anatomically discontinuous, but they remain functionally connected because membranous and lumenal material is moved from one compartment to another by means of transport vesicles. For example, proteins and phospholipids synthesized in the rough endoplasmic reticulum (the portion of the reticulum nearest the nucleus and studded with ribosomes) and the smooth endoplasmic reticulum are transported to the Golgi complex and then to secretory vesicles, which empty their contents when the vesicle membrane fuses with the plasmalemma (a process called exocytosis). This secretory pathway serves to add membranous components to the plasmalemma and also to discharge any contents of the secretory vesicles into the extracellular space.

Conversely, plasmalemmal membrane is taken into the cell in the form of endocytic vesicles (endocytosis). These are incorporated into early endosomes, sorting compartments that are concentrated at the cell's periphery. The incorporated membrane, which typically contains specific proteins such as receptors, is then either shuttled back to the plasmalemma by vesicles for recycling or directed to late endosomes and eventually to mature lysosomes for degradation. (Exocytosis and endocytosis are discussed in detail later in this chapter and in Chapter 12.) The smooth endoplasmic reticulum also acts as a regulated internal Ca²⁺ store throughout the neuronal cytoplasm (see Chapter 11 on Ca²⁺ release).

A specialized portion of the rough endoplasmic reticulum forms the nuclear envelope, a spherical flattened cisterna that surrounds chromosomal DNA and its associated proteins (histones, transcription factors, polymerases, and isomerases) and defines the nucleus (Figure 4–1). Because the nuclear envelope is continuous with other portions of the endoplasmic reticulum and to the other membranes of the vacuolar apparatus, it is presumed to have evolved as an invagination of the plasmalemma to ensheathe eukaryotic chromosomes. The nuclear envelope is interrupted by nuclear pores, where fusion of the inner and outer membranes of the envelope results in the formation of hydrophilic channels through which proteins and RNA are exchanged between the cytoplasm proper and the nuclear cytoplasm.

Even though nucleoplasm and cytoplasm are continuous domains of cytosol, only molecules with molecular weights less than 5,000 can pass through the nuclear pores freely by diffusion. Larger molecules need help. Some proteins have special nuclear localization signals, domains that are composed of a sequence of basic amino acids (arginine and lysine) that are recognized by soluble proteins called nuclear import receptors (importins). At a nuclear pore this complex is guided into the nucleus by another group of proteins called nucleoporins.

The cytoplasm of the nerve cell body extends into the dendritic tree without functional differentiation. Generally, all organelles in the cytoplasm of the cell body are also present in dendrites, although the densities of the rough endoplasmic reticulum, Golgi complex, and lysosomes rapidly diminish with distance from the cell body. In dendrites the smooth endoplasmic reticulum is prominent at the base of thin processes called spines (Figures 4–3 and 4–4), the receptive portion of excitatory synapses. Concentrations of polyri bosomes in dendritic spines are presumed to serve local protein synthesis (see below and Figure 4–4).

Figure 4–3

Golgi and endoplasmic reticulum membranes extend from the cell body into dendrites.

A. The Golgi complex (solid arrow) appears under the light microscope as several filaments that extend into the dendrites (open arrow) but not into the axon. The arrowheads at the bottom indicate the axon hillock. For this micrograph a large neuron of the brain stem was immunostained with antibodies specifically directed against the Golgi complex. (Reproduced, with permission, from De Camilli et al. 1986.)

B. Smooth endoplasmic reticulum (arrowhead) extends into the neck of a dendritic spine, while another membrane compartment sits at the origin of the spine (arrow). (Reproduced, with permission, from Cooney et al. 2002.)

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Figure 4–4

Types of dendritic spines.

Three types of dendritic spine shapes are shown in a mature dendrite in a pyramidal cell in the CA1 region of the hippocampus. The drawing is based on a series of electron micrographs. (Reproduced, with permission, from Harris and Stevens 1989.)

A. In this thin dendritic spine the thickened receptive surface (open arrow), located across from the presynaptic axon, contains synaptic receptors. The tissue shown here and in B and C is from the hippocampus of a postnatal day-15 rat brain.

B. Stubby spines containing postsynaptic densities (arrow) are both small and rare in the mature hippocampus. Their larger counterparts (not shown) predominate in the immature brain.

C. Mushroom-shaped spines have a larger head. The immature spine shown here contains flat cisternae of smooth endoplasmic reticulum, some with a beaded appearance (solid arrow). The postsynaptic density is indicated by the open arrow. (A, B, and C are reproduced, with permission, from Sorra and Harris 1993.)

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In contrast to the continuity of the cell body and dendrites, a sharp functional boundary exists between the cell body at the axon hillock, where the axon emerges. Ribosomes, rough endoplasmic reticulum, and the Golgi complex—the organelles that comprise the main biosynthetic machinery for proteins in the neuron—are generally excluded from axons (see Figure 4–3). Lysosomes and certain proteins are also excluded. However, axons are rich in synaptic vesicles and their precursor membranes.

The Cytoskeleton Determines Cell Shape

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The cytoskeleton determines the shape of a cell and is responsible for the asymmetric distribution of organelles within the cytoplasm. It includes three filamentous structures: microtubules, neurofilaments, and microfilaments. These filaments and associated proteins account for approximately a quarter of the total protein in the cell.

Microtubules form long scaffolds that extend from one end of a neuron to the other and play a key role in developing and maintaining cell shape. A single microtubule can be as long as 0.1 mm. Microtubules are constructed of protofilaments, each of which consists of multiple pairs of α- and β-tubulin subunits arranged longitudinally along the microtubule (Figure 4–5A). Tubulin subunits bind to neighboring subunits along the protofilament and also laterally between adjacent protofilaments. The tubulin dimer has a polar structure: The negative end is oriented to the center of the cell while the positive end extends out to the periphery, to the dendrites and axon.

Figure 4–5

Atlas of fibrillary structures.

A. Microtubules, the largest-diameter fibers (25 nm), are helical cylinders composed of 13 protofilaments, each 5 nm in width. Each protofilament is made up of a column of alternating α- and β-tubulin subunits (each subunit has a molecular weight of approximately 50,000). Adjacent subunits bind to each along the longitudinal protofilaments and laterally between subunits of adjacent protofilaments.

A tubulin molecule is a heterodimer consisting of one α- and one β-tubulin subunit. 1. View of a microtubule. The arrows indicate the direction of the right-handed helix. 2. A side-view of a microtubule shows the alternating α- and β-subunits.

B. Neurofilaments are built with fibers that twist around each other to produce coils of increasing thickness. The thinnest units are monomers that form coiled-coil heterodimers. These dimers form a tetrameric complex that becomes the protofilament. Two protofilaments become a protofibril, and three protofibrils are helically twisted to form the 10 nm diameter neurofilament. (Adapted, with permission, from Bershadsky and Vasiliev 1988.)

C. Microfilaments, the smallest diameter fibers (approximately 7 nm), are composed of two strands of polymerized globular actin (G-actin) monomers arranged in a helix. At least six different (but closely related) actins are found in mammals. Each variant is encoded by a separate gene. Microfilaments are polar structures because the globular monomers are asymmetric.

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Microtubules grow by addition of guanosine triphosphate (GTP)-bound tubulin dimers at their positive end, the end that points to the periphery. Shortly after polymerization the GTP is hydrolyzed to guanosine diphosphate (GDP). When a microtubule stops growing, its positive end is capped by a GDP-bound tubulin monomer. Given the low affinity of the GDP-bound tubulin for the polymer, this would lead to catastrophic depolymerization unless the microtubules were stabilized by interaction with other proteins.

In fact, while microtubules undergo rapid cycles of polymerization and depolymerization in dividing cells, in mature dendrites and axons they are much more stable. This stability is caused by microtubule-associated proteins (MAPs) that promote the oriented polymerization and assembly of the tubulin polymers. MAPs in axons differ from those in dendrites. For example, MAP2 is present in dendrites but not in axons, whereas tau and MAP3 are present. In Alzheimer disease and some other degenerative disorders tau proteins are modified and abnormally polymerized, forming a characteristic lesion called the neurofibrillary tangle (Box 4–1).

Box 4–1 Abnormal Accumulations of Proteins Are Hallmarks of Many Neurological Disorders

Tau is a microtubule-binding protein normally present in nerve cells. In Alzheimer disease abnormal aggregates of tau are visible in the light microscope in neurons and glia as well as in the extracellular space. Highly phosphorylated tau molecules arranged in long, thin polymers wind around one another to form paired helical filaments (Figure 4–6A and see Chapter 59). Bundles of the polymers, known as neurofibrillary tangles, accumulate in neuronal cell bodies, dendrites, and axons (Figure 4–6A).

In normal neurons tau is either bound to microtubules or free in the cytosol. In the tangles it is not bound to microtubules but is highly insoluble. The tangles form at least in part because tau is not proteolytically degraded. The accumulations disturb the polymerization of tubulin and therefore interfere with axonal transport. Consequently, the shape of the neuron is not maintained.

Tau accumulations are also found in neurons of patients with progressive supranuclear palsy, a movement disorder, and in patients with frontotemporal dementias, a group of neurodegenerative disorders that affect the frontal and temporal lobes (see Chapter 59). The familial forms of fronto temporal dementias are caused by mutations in the tau gene. Abnormal aggregates are also found in glial cells, both astrocytes and oligodendrocytes, in progressive supranuclear palsy, cortico-basoganglionic degeneration, and fronto temporal dementias.

The peptide β-amyloid also accumulates in the extracellular space in Alzheimer disease (Figure 4–6B and see Chapter 57). It is a small proteolytic product of a much larger integral membrane protein, amyloid precursor protein, which is normally processed by several proteolytic enzymes associated with intracellular membranes. The proteolytic pathway that generates β-amyloid requires the enzyme β-secretase.

For unknown reasons, in Alzheimer disease abnormal amounts of the amyloid precursor are processed by β-secretase. Some patients with early-onset familial Alzheimer disease either have mutations in the amyloid precursor gene or in the genes coding for the membrane proteins presenilin 1 and 2, which are closely associated with β-secretase activity.

In Parkinson disease abnormal aggregates of α-synuclein accumulate in cell bodies of neurons. Like tau, α-synuclein is a normal soluble constituent of the cell. But in Parkinson disease it becomes insoluble, forming spherical inclusions called Lewy bodies (Figure 4–6C and see Chapter 44).

These abnormal inclusions also contain ubiquitin. Because ubiquitin is required for proteasomal degradation of proteins, its presence suggests that affected neurons have attempted to target α-synuclein or other molecular constituents for proteolysis. Apparently, degradation does not occur, possibly because of misfolding or the abnormal aggregation of the proteins or because of faulty proteolytic processing in the cell.

Do these abnormal protein accumulations affect the physiology of the neurons and glia? On the one hand, the accumulations may form in response to altered post-translational processing of the proteins and serve to isolate the abnormal proteins, permitting normal cell activities. On the other hand, the accumulations may disrupt cellular activities such as membrane trafficking and axonal and dendritic transport. In addition, the altered proteins themselves, aside from the aggregations, may have deleterious effects. With β-amyloid there is evidence that the peptide itself is toxic.

Figure 4–6

Abnormal aggregates of proteins inside neurons in Alzheimer and Parkinson diseases.

A. Intracellular neurofibrillary tangles of Alzheimer disease, labeled here with a dark silver stain (left). (Reproduced, with permission, from J.P. Vonsattel.) The electron micrograph of a tangle (right) shows the bundles of abnormal filaments, here filling a dendrite. The filaments are composed of altered tau protein. (Reproduced, with permission, from Esiri et al. 2002.)

B. Extracellular deposits of polymerized β-amyloid peptides in Alzheimer disease create an amyloid plaque. This plaque has a dense core of amyloid as well as a surrounding halo of deposits. Note the neuronal processes in the plaque with tangle pathology. (Reproduced, with permission, from J.P. Vonsattel.)

C. A Lewy body in the substantia nigra of a patient with Parkinson disease contains accumulations of abnormal filaments made up of α-synuclein, among other proteins. (Reproduced, with permission, from J.P. Vonsattel.)

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Tubulins are encoded by a multigene family. At least six genes code the α- and β-subunits. Because of the expression of the different genes or post transcriptional modifications more than 20 isoforms of tubulin are present in the brain.

Neurofilaments, 10 nm in diameter, are the bones of the cytoskeleton (see Figure 4–5B). They are the most abundant fibrillar component in axons; on average there are 3 to 10 times more neurofilaments than microtubules in an axon. Neurofilaments are related to intermediate filaments of other cell types, including the cytokeratins of epithelial cells (hair and nails), glial fibrillary acidic protein in astrocytes, and desmin in muscle. Unlike microtubules, neurofilaments are stable and almost totally polymerized in the cell.

At 3–7 nm in diameter microfilaments are the thinnest of the three main types of fibers that make up the cytoskeleton (Figure 4–5C). Like thin filaments of muscle, microfilaments are made up of two strands of polymerized globular actin monomers, each bearing an ATP or adenosine diphosphate (ADP), wound into a double-stranded helix. Actin is a major constituent of all cells, perhaps the most abundant animal protein in nature. There are several closely related molecular forms: the α actin of skeletal muscle and at least two other molecular forms, β and γ. Each is encoded by a different gene. Neural actin in higher vertebrates is a mixture of the β and γ species, which differ from muscle actin by a few amino acid residues. Most actin molecules are highly conserved, not only in different cell types of a species but also in organisms as distantly related as humans and protozoa.

Unlike microtubules and neurofilaments, actin filaments are short. They are concentrated at the cell's periphery in the cortical cytoplasm just underneath the plasmalemma, where they form a dense network with many actin-binding proteins (eg, spectrin-fodrin, ankyrin, talin, and actinin). This matrix plays a key role in the dynamic function of the cell's periphery, such as the motility of growth cones (the growing tips of axons) during development, generation of specialized microdomains at the cell surface, and the formation of pre- and postsynaptic morphological specializations.

Like microtubules, microfilaments undergo cycles of polymerization and depolymerization. At any one time approximately half the total actin in a cell can exist as unpolymerized monomers. The state of actin is controlled by binding proteins, which facilitate assembly and limit polymer length by capping the rapidly growing end of the filament or by severing it. Other binding proteins crosslink or bundle microfilaments. The dynamic state of microtubules and microfilaments permits a mature neuron to retract old axons and dendrites and extend new ones. This structural plasticity is thought to be a major factor in changes of synaptic connections and efficacy, and therefore cellular mechanisms of long-term memory and learning.

In addition to serving as cytoskeleton, microtubules and actin filaments act as tracks along which organelles and proteins are rapidly driven by molecular motors. The motors used by the actin filaments, the myosins, also mediate other types of cell motility, including extension of the cell's processes, and the translocation of membranous organelles from the bulk cytoplasm to the region adjacent to the plasma membrane. (Actomyosin is responsible for muscle contraction.) Because the microtubules and actin filaments are polar, each motor drives its organelle cargo in only one direction.

As already mentioned, microtubules are arranged in parallel in the axon with positive ends pointing away from the cell body and negative ends facing the cell body. This regular orientation permits some organelles to move toward nerve endings and others to move away from nerve endings, the direction being determined by the specific type of molecule motor, thus maintaining the distinctive distribution of axonal organelles (Figure 4–7). In dendrites, however, microtubules with opposite polarities are mixed together, explaining why the organelles of the cell body and dendrites are similar.

Figure 4–7

The cytoskeletal structure of an axon.

The micrograph shows the dense packing of microtubules and neurofilaments linked by cross bridges (arrows). Organelles are transported in both the anterograde and retrograde directions in the microtubule-rich domains. Visualization in the micrograph was achieved by quick freezing and deep etching. M, myelin sheath; MT, microtubules × 105,000. (Adapted, with permission, from Schnapp and Reese 1982.)

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Protein Particles and Organelles Are Actively Transported Along the Axon and Dendrites

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In neurons most proteins are made in the cell body from mRNAs in the cell body. Important examples are synthesis of neurotransmitter biosynthetic enzymes, synaptic vesicle membrane components, and neurosecretory peptides. Because axons and terminals often lie at great distances from the cell body, transport mechanisms are crucial for sustaining the function of these remote regions.

The axon terminal, the site of secretion most important for neuronal signaling, is considerably distant from the cell body. For example, in a motor neuron that innervates a muscle of the leg in humans, the distance of the nerve terminal from the cell body can exceed 10,000 times the cell-body diameter. Passive diffusion is far too slow to deliver vesicles, particles, or even single macromolecules over this great distance. Membrane and secretory products formed in the cell body must be actively transported to the end of the axon (Figure 4–8).

Figure 4–8

Membrane trafficking in the neuron.

1. Proteins and lipids of secretory organelles are synthesized in the endoplasmic reticulum and transported to the Golgi complex, where large dense-core vesicles (peptide-containing secretory granules) and synaptic vesicle precursors are assembled. 2. Large dense-core vesicles and transport vesicles that carry synaptic vesicle proteins travel down the axon via axonal transport. 3. At the nerve terminals the synaptic vesicles are assembled and loaded with nonpeptide neurotransmitters. Synaptic vesicles and large dense-core vesicles release their contents by exocytosis. 4. Following exocytosis, large dense-core vesicle membranes are returned to the cell body for reuse or degradation. Synaptic vesicle membranes undergo many cycles of local exocytosis and endocytosis in the presynaptic terminal.

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In 1948 Paul Weiss first demonstrated axonal transport when he tied off a sciatic nerve and observed that axoplasm in the nerve accumulated with time on the proximal side of the ligature. He concluded that axoplasm moves at a slow, constant rate from the cell body toward terminals in a process he called axoplasmic flow. Today we know that the flow Weiss observed consists of two discrete mechanisms, one fast and the other slow.

Membranous organelles move toward terminals (anterograde direction) and back toward the cell body (retrograde direction) by fast axonal transport, a form of transport that is faster than 400 mm per day in warm-blooded animals. In contrast, cytosolic and cytoskeletal proteins move only in the anterograde direction by a much slower form of transport, slow axonal transport. These transport mechanisms in neurons are adaptations of processes that facilitate intracellular movement of organelles in all secretory cells. Because these mechanisms all operate along axons, they have been used by neuroanatomists to trace the axon distribution of neurons (Box 4–2).

Box 4–2 Neuroanatomical Tracing Makes Use of Axonal Transport

Neuroanatomists typically locate axons and terminals of specific nerve cell bodies by microinjection of dyes; expression of fluorescent proteins; or autoradiographically tracing specific proteins soon after administering radioactively labeled amino acids, certain labeled sugars (fucose or amino sugars, precursors of glycoprotein), or specific transmitter substances.

Similarly, particles, proteins, or dyes that are readily taken up at nerve terminals by endocytosis and transported back to cell bodies are used to identify the cell bodies. The enzyme horseradish peroxidase has been most widely used for this type of study because it readily undergoes retrograde transport and its reaction product is conveniently visualized histochemically.

Axonal transport is also used by neuroanatomists to label material exchanged between neurons, making it possible to identify neuronal networks (Figure 4–9).

Figure 4–9

Axonal transport of the herpes simplex virus (HSV) is used to trace cortical pathways in monkeys.

Depending on the strain, the virus moves in the anterograde or retrograde direction by axonal transport. In either direction it enters a neuron with which the infected cell makes synaptic contact. Here the projections of cells in the primary motor cortex to the cerebellum in monkeys were traced using an anterograde-moving strain (HSV-1 [H129]). Monkeys were injected in the region of the primary motor cortex that controls the arm. After 4 days the brain was sectioned and immunostained for viral antigen. Micrographs show the virus was transported from the primary motor cortex to second-order neurons in pontine nuclei (A) and then to third-order neurons in the cerebellar cortex (B). (Reproduced, with permission, from P. L. Strick.)

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Fast Axonal Transport Carries Membranous Organelles

Large membranous organelles are carried to and from the axon terminals by fast transport (Figure 4–10). These organelles include synaptic vesicle precursors, large dense-core vesicles, mitochondria, elements of the smooth endoplasmic reticulum, as well as protein particles carrying RNAs. Direct microscopic analysis reveals that fast transport occurs in a stop-and-start (saltatory) fashion along linear tracks of microtubules aligned with the main axis of the axon. The saltatory nature of the movement results from the periodic dissociation of an organelle from the track or from collisions with other particles.

Figure 4–10

Early experiments on anterograde axonal transport used radioactive labeling of proteins.

In the experiment illustrated here the distribution of radioactive proteins along the sciatic nerve of the cat was measured at various times after injection of [³H]-leucine into dorsal root ganglia in the lumbar region of the spinal cord. To show transport curves from various times (2, 4, 6, 8, and 10 hours after the injection) in one figure, several ordinate scales (in logarithmic units) are used. Large amounts of labeled protein stay in the ganglion cell bodies but, with time, move out along axons in the sciatic nerve, so the advancing front of the labeled protein is progressively farther from the cell body (black arrows). The velocity of transport can be calculated from the distances of the front displayed at the various times. From experiments of this kind Sidney Ochs found that the rate of fast axonal transport is constant at 410 mm per day at body temperature. (Adapted, with permission, from Ochs 1972.)

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Early experiments on dorsal root ganglion cells showed that anterograde fast transport depends critically on ATP, is not affected by inhibitors of protein synthesis (once the labeled amino acid injected is incorporated), and does not depend on the cell body, because it occurs in axons severed from their cell bodies. In fact, active transport can occur in reconstituted cell-free axoplasm.

Microtubules provide an essentially stationary track on which specific organelles can be moved by molecular motors. The idea that microtubules are involved in fast transport emerged from the finding that certain alkaloids that disrupt microtubules and block mitosis, which depends on microtubules, also interfere with fast transport.

Molecular motors were first visualized in electron micrographs as cross bridges between microtubules and moving particles (Figure 4–7). The motor molecules for anterograde transport (toward the positive end of microtubules) are kinesin and a variety of kinesin-related proteins. The kinesins represent a large family of adenosine triphosphatases (ATPase), each of which transports different cargoes. Kinesin is a hetero tetramer composed of two heavy chains and two light chains. Each heavy chain has three domains: (1) a globular head (the ATPase domain) that acts as the motor when attached to microtubules, (2) a coiled-coil helical stalk responsible for dimerization with the other heavy chain, and (3) a fan-like carboxyl-terminus that interacts with the light chains.

The organelles moved by retrograde fast transport are primarily endosomes generated by endocytic activity at nerve endings, mitochondria, and elements of the endoplasmic reticulum. Many of these components degrade in lysosomes. Retrograde fast transport also delivers signals that regulate gene expression in the neuron's nucleus. For example, activated growth factor receptors are taken up into vesicles at nerve endings and carried back along the axon to their site of action in the nucleus. Transport of transcription factors informs the gene transcription apparatus in the nucleus of conditions in the periphery. Retrograde transport of these molecules is especially important during nerve regeneration and axon regrowth (see Chapter 54). Certain toxins (tetanus toxin) as well as pathogens (herpes simplex, rabies, and polio viruses) are also transported toward the cell body along the axon.

The rate of retrograde fast transport is approximately one-half to two-thirds that of anterograde fast transport. As in anterograde transport, particles move along microtubules. The motor molecule for retrograde transport is a microtubule-associated ATPase called MAP-1C. This molecule is similar to the dyneins in cilia and flagella of other cells and consists of a multimeric protein complex with two globular heads on two stalks connected to a basal structure. The globular heads attach to microtubules and act as motors, moving toward the negative end of the polymer. As with kinesin, the other end of the complex attaches to the organelle being moved.

Microtubules also transport mRNAs and ribosomal RNA carried in particles formed with RNA-binding proteins. These proteins have been characterized in both vertebrate and invertebrate nervous systems and include the cytoplasmic polyadenylation element binding protein (CPEB), the fragile X protein, Hu proteins, NOVA, and Staufen. The activities of these proteins are critical. Humans with mutations in the fragile X gene are mentally retarded and have spinal defects. For example, CPEB keeps select mRNAs dormant during transport from the cell body to nerve endings; once there (upon stimulation), the binding protein can facilitate the local translation of the RNA by mediating polyadenylation and activation of the messenger. Both CPEB and Staufen were discovered in Drosophila where they maintain maternal mRNAs dormant in unfertilized eggs and, upon fertilization, distribute and localize mRNA to various regions of the dividing embryo.

Proteins, ribosomes, and mRNA are concentrated at the base of dendritic spines (Figure 4–11). Only a select group of mRNA are transported to the nerve terminals. These include mRNA for actin- and cytoskeletal- associated proteins MAP2 and the α-subunit of the Ca²⁺/calmodulin-dependent protein kinase. They are translated in the dendrites in response to activity in a presynaptic neuron. This local protein synthesis is thought to be important in sustaining the molecular changes at the synapse that underlie long-term memory and learning. Likewise, the mRNA for myelin basic protein is transported to the distant ends of the oligodendrocytes, where it is translated as the myelin sheath grows, as discussed later in this chapter.

Figure 4–11

Ribosomes in the dendritic arbor.

(Images reproduced, with permission, from Oswald Steward.)

A. Some ribosomes are dispatched from the cell body to dendrites where they are used in local protein synthesis. This autoradiograph shows the distribution of ribosomal RNA (rRNA) in hippocampal neurons in low-density cultures using in situ hybridization. The photomicrograph was taken with dark field illumination, in which silver grains reflect light and thus appear as bright spots. Silver grains, denoting the rRNA, are heavily concentrated over cell bodies and dendrites but are not detectable over the axons that crisscross among the dendrites.

B. Ribosomes in dendrites are selectively concentrated at the junction of the spine and main dendritic shaft (arrow), where the spine contacts the axon terminal of a presynaptic neuron. This electron micrograph shows a mushroom-shaped spine of a neuron in the hippocampal dentate gyrus. Note the absence of ribosomes in the dendritic shaft. S, spine head; T, presynaptic terminal; Den, main shaft of the dendrite containing a long mitochondrion. × 60,000.

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Slow Axonal Transport Carries Cytosolic Proteins and Elements of the Cytoskeleton

Cytosolic proteins and cytoskeletal proteins are moved from the cell body by slow axonal transport. Slow transport occurs only in the anterograde direction and consists of at least two kinetic components that carry different proteins at different rates.

The slower component travels at 0.2 to 2.5 mm per day and carries the proteins that make up the fibrillar elements of the cytoskeleton: the subunits of neurofilaments and α- and β-tubulin subunits of microtubules. These fibrous proteins constitute approximately 75% of the total protein moved in the slower component. Microtubules are transported in polymerized form by a mechanism involving microtubule sliding in which relatively short preassembled microtubules move along existing microtubules. Neurofilament monomers or short polymers move passively together with the microtubules because they are cross-linked by protein bridges.

The other component of slow axonal transport is approximately twice as fast as the slower. It carries clathrin, actin, and actin-binding proteins as well as a variety of enzymes and other proteins.

Proteins Are Made in Neurons as in Other Secretory Cells

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Secretory and Membrane Proteins Are Synthesized and Modified in the Endoplasmic Reticulum

The mRNAs for secretory and membrane proteins are translated in conjunction with the membrane of the rough endoplasmic reticulum, and their polypeptide products are processed extensively within the lumen of the endoplasmic reticulum. Most polypeptides destined to become proteins are translocated across the membrane of the rough endoplasmic reticulum during synthesis, a process called cotranslational transfer.

Transfer is possible because ribosomes, the site where proteins are synthesized, attach to the cytosolic surface of the reticulum (Figure 4–12). Complete transfer of the polypeptide chain into the lumen of the reticulum produces a secretory protein (recall that the inside of the reticulum is related to the outside of the cell). Important examples are the neuroactive peptides. If the transfer is incomplete, an integral membrane protein results. Because a polypeptide chain can thread its way through the membrane many times during synthesis, several membrane-spanning configurations are possible depending on the primary amino acid sequence of the protein. Important examples are neurotransmitter receptors and ion channels (see Chapter 5).

Figure 4–12

Protein synthesis in the endoplasmic reticulum.

Free and membrane-bound polysomes translate mRNA that encodes proteins with a variety of destinations. Messenger RNA, transcribed from genomic DNA in the neuron's nucleus, emerges into the cytoplasm through nuclear pores (enlargement) to form polyribosomes. The polypeptides that become secretory and membrane proteins are translocated across the membrane of the rough endoplasmic reticulum.

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Some proteins transported into the endoplasmic reticulum remain there. Others are moved to other compartments of the vacuolar apparatus or to the plasmalemma, or are secreted into the extracellular space. Proteins that are processed in the endoplasmic reticulum are extensively modified. One important modification is the formation of intramolecular disulfide linkages (Cys-S-S-Cys) caused by oxidation of pairs of free sulfhydryl side chains, a process that cannot occur in the reducing environment of the cytosol. Disulfide linkages are crucial to the tertiary structure of these proteins.

Proteins may be modified by cytosolic enzymes either during synthesis (cotranslational modification) or afterward (post-translational modification). One example is N-acylation, the transfer of an acyl group to the N-terminus of the growing polypeptide chain. Acylation by a 14-carbon fatty acid myristoyl group permits the protein to anchor in membranes through the lipid chain.

Other fatty acids can be conjugated to the sulfhydryl group of cysteine, producing a thioacylation:

Isoprenylation is another post-translational modification important for anchoring proteins to the cytosolic side of membranes. It occurs shortly after synthesis of the protein is completed and involves a series of enzymatic steps that result in thioacylation by one of two long-chain hydrophobic polyisoprenyl moieties (farnesyl, with 15 carbons, or geranyl-geranyl, with 20) of the sulfhydryl group of a cysteine at the C-terminus of proteins.

Some post-translational modifications are readily reversible and thus used to regulate the function of a protein transiently. The most common of these modifications is the phosphorylation at the hydroxyl group in serine, threonine, or tyrosine residues by protein kinases. Dephosphorylation is catalyzed by protein phosphatases. (These reactions are discussed in Chapter 11.) As with all post-translational modifications, the sites to be phosphorylated are determined by particular sequences of amino acids around the residue to be modified. Phosphorylation can alter physiological processes in a reversible fashion. For example, protein phosphorylation-dephosphorylation reactions regulate the kinetics of ion channels, the activity of transcription factors, and the assembly of the cytoskeleton.

Still another important post-translational modification is the addition of ubiquitin, a highly conserved protein with 76 amino acids, to the ∈-amino group of specific lysine residues in the protein molecule. Ubiquitination, which regulates protein degradation, is mediated by three enzymes. E1 is an activating enzyme that uses the energy of ATP. The activated ubiquitin is next transferred to a conjugase, E2, which then transfers the activated moiety to a ligase, E3. E3 alone or together with the E2 transfers the ubiquitinyl group to the lysine residue in a protein. Specificity arises because a given protein molecule can only be ubiquinated by a specific E3 or combination of E3 and E2. Some E3s also require special cofactors—ubiquitination occurs only in the presence of E3 and a cofactor protein.

Monoubiquitination tags a protein for degradation in the endosomal-lysosomal system. This is especially important in endocytosis and recycling of surface receptors. Ubiquitinyl monomers are successively linked to the ∈-amino group of a lysine residue in the previously added ubiquitin moiety. Addition of more than five ubiquitins to the multiubiquitin chain tags the protein for degradation by the proteasome, a large complex containing multifunctional protease subunits that cleave proteins into short peptides.

The ATP-ubiquitin-proteasome pathway is a mechanism for the selective and regulated proteolysis of proteins that operates in the cytosol of all regions of the neuron—dendrites, cell body, axon, and terminals. Until recently this process was thought to be primarily directed to poorly folded, denatured, or aged and damaged proteins. We now know that ubiquitin-mediated proteolysis can be regulated by neuronal activity and plays specific roles in many neuronal processes, including synaptogenesis and long-term memory storage.

Another important protein modification is glycosylation, which occurs on amino groups of asparagine residues (N-linked glycosylation) and results in the addition en bloc of complex polysaccharide chains. These chains are then trimmed within the endoplasmic reticulum by a series of reactions controlled by chaperones, including heat shock proteins, calnexin, and calreticulin. Because of the great chemical specificities of oligosaccharide moieties, these modifications can have important implications for cell function. For example, cell-to-cell interactions that occur during development rely on molecular recognition between glycoproteins on the surfaces of the two interacting cells. Also, because a given protein can have somewhat different oligosaccharide chains, glycosylation can diversify the function of a protein. It can increase the hydrophilicity of the protein (useful for secretory proteins), fine-tune its ability to bind macromolecular partners, and delay its degradation.

An interesting post-translational modification of mRNA is RNA interference (RNAi), the targeted destruction of double-stranded RNAs. This mechanism, which is believed to have arisen to protect cells against viruses and other rogue fragments of nucleic acids, shuts down the synthesis of any targeted protein. Double-stranded RNAs are taken up by an enzyme complex that cleaves the molecule into oligomers. The RNA sequences are retained by the complex. As a result, any homologous hybridizing RNA strands, either double- or single-stranded, will be destroyed. The process is regenerative: The complex retains a hybridizing fragment and goes on to destroy another RNA molecule until none remain in the cell. Although the physiological role of RNA interference (RNAi) in normal cells is unclear, transfection or injection of RNAi into cells is of great research and clinical importance (see Chapter 3).

Secretory Proteins Are Modified in the Golgi Complex

Proteins from the endoplasmic reticulum are carried in transport vesicles to the Golgi complex where they are modified and then moved to synaptic terminals and other parts of the plasmalemma. The Golgi complex appears as a grouping of membranous sacks aligned with one another in long ribbons.

The mechanism by which vesicles are transported between stations of the secretory and endocytic pathways is remarkably conserved from simple unicellular prokaryotes (yeast) to neurons and glia of multicellular organisms. Transport vesicles develop from membrane, beginning with the assembly of proteins that form coats, or coat proteins, at selected patches of the cytosolic surface of the membrane. A coat has two functions. It forms rigid cage-like structures that produce evagination of the membrane into a bud shape and it selects the protein cargo to be incorporated into the vesicles.

There are several types of coats. Clathrin coats assist in evaginating Golgi complex membrane and plasmalemma during endocytosis. Two other coats, COPI and COPII, cover transport vesicles that shuttle between the endoplasmic reticulum and the Golgi complex. Coats usually are rapidly dissolved once free vesicles have formed. The fusion of vesicles with the target membrane is mediated by a cascade of molecular interactions, the most important of which is the reciprocal recognition of small proteins on the cytosolic surfaces of the two interacting membranes: vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptors (v-SNAREs) and t-SNAREs (target-membrane SNAREs). The actions of these small proteins are discussed in Chapter 12 in connection with how synaptic vesicles release neurotransmitters at synapses.

Vesicles from the endoplasmic reticulum arrive at the cis side of the Golgi complex (the aspect facing the nucleus) and fuse with its membranes to deliver their contents into the Golgi complex. These proteins travel from one Golgi compartment (cisterna) to the next, from the cis to the trans side, undergoing a series of enzymatic reactions. Each Golgi cisterna or set of cisternae is specialized for a particular type of reaction. Several types of protein modifications, some of which begin in the endoplasmic reticulum, occur within the Golgi complex proper or within the transport station adjacent to its trans side, the trans-Golgi network (the aspect of the complex typically facing away from the nucleus toward the axon hillock). These modifications include the addition of N-linked oligosaccharides, O-linked (on the hydroxyl groups of serine and threonine) glycosylation, phosphorylation, and sulfation.

Both soluble and membrane-bound proteins that travel through the Golgi complex emerge from the trans-Golgi network in a variety of vesicles that have different molecular compositions and destinations. Proteins transported from the trans-Golgi network include secretory products as well as newly synthesized components for the plasmalemma, endosomes, and other membranous organelles (see Figure 4–1). One class of vesicles carries newly synthesized plasmalemmal proteins and proteins that are continuously secreted (constitutive secretion). These vesicles fuse with the plasmalemma in an unregulated fashion. An important type of these vesicles delivers lysosomal enzymes to late endosomes.

Still other classes of vesicles carry secretory proteins that are released by an extracellular stimulus (regulated secretion). One type stores secretory products, primarily neuroactive peptides in high concentrations. Called large dense-core vesicles because of their electron-dense (osmophilic) appearance in the electron microscope, these vesicles are similar in function and biogenesis to peptide-containing granules of endocrine cells. Large dense-core vesicles are targeted primarily to axons but can be seen in all regions of the neuron. They accumulate in the cytoplasm just beneath the plasma membrane and are highly concentrated at axon terminals, where they undergo Ca²⁺-regulated exocytosis (see Figure 4–8). The optimal stimulus for their secretion is a train of action potentials.

An important, but as yet unanswered, question is how synaptic vesicles—the small lucent vesicles responsible for the rapid release of neurotransmitter at axon terminals—reach the terminals. It is thought that proteins that make up synaptic vesicles are carried to endosomes and the plasmalemma of axon terminals in large precursor vesicles from the trans-Golgi network. Once at the terminals the proteins are processed into synaptic vesicles as they pass through endosomes during the exocytosis/recycling process described in Chapter 12. The neurotransmitter molecules stored in synaptic vesicles are released by exocytosis regulated by Ca²⁺ influx through channels close to the release site.

Surface Membrane and Extracellular Substances Are Recycled in the Cell

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Vesicular traffic toward the cell surface is continuously balanced by endocytic traffic from the plasmalemma to internal organelles. This traffic is essential for maintaining the area of the plasmalemma in a steady state. It can alter the activity of many important regulatory molecules on the cell surface (eg, by removing receptors and adhesion molecules). It also removes nutrients and molecules, such as expendable receptor ligands and damaged membrane proteins, to the degradative compartments of the cells. Finally, it serves to recycle synaptic vesicles at nerve terminals (see Chapter 12).

A significant fraction of endocytic traffic is carried in clathrin-coated vesicles. The clathrin coat interacts selectively through transmembrane receptors with extracellular molecules that are to be taken up into the cell. For this reason clathrin-mediated uptake is often referred to as receptor-mediated endocytosis. The vesicles eventually shed their clathrin coats and fuse with the early endosomes, in which proteins to be recycled to the cell surface are separated from those destined for other intracellular organelles. Patches of the plasmalemma can also be recycled through larger, uncoated vacuoles that also fuse with early endosomes (bulk endocytosis).

Glial Cells Play Diverse Roles in Neural Function

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Glia Form the Insulating Sheaths for Axons

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.

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).

Figure 4–13

Myelin insulates the axons of both central and peripheral neurons.

A. Axons in the central nervous system are wrapped in several layers of myelin produced by oligodendrocytes. Each oligo dendrocyte can myelinate many axons. (Reproduced, with permission, from Raine 1984.)

B. This electron micrograph of a transverse section through an axon (Ax) in the sciatic nerve of a mouse shows the origin of a sheet of myelin (MI) at a structure called the inner mesaxon (IM). The sheet arises from the surface membrane (SM) of a Schwann cell, which is continuous with the outer mesaxon (OM). The Schwann cell cytoplasm (Sc Cyt) still surrounds the axon; eventually, it is squeezed out and the myelin layers become compact. (Reproduced, with permission, from Dyck et al. 1984.)

C. A peripheral nerve fiber is myelinated by a Schwann cell in several stages. In stage 1 the Schwann cell surrounds the axon. In stage 2 the outer aspects of the plasma membrane have become tightly apposed in one area. This membrane fusion reflects early myelin membrane formation. In stage 3 several layers of myelin have formed because of continued rotation of the Schwann cell cytoplasm around the axon. In stage 4 a mature myelin sheath has formed; much of the Schwann cell cytoplasm has been squeezed out of the innermost loop. (Adapted, with permission, from Williams et al. 1989.)

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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).

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.

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.

Figure 4–14

The myelin sheath of axons has regular gaps called the nodes of Ranvier.

A. Electron micrographs show the region of nodes in axons from the peripheral nervous system and spinal cord. The axon (Ax) runs vertically in both micrographs. The layers of myelin (M) are absent at the nodes (Nd), where the axon's membrane (axolemma, Al) is exposed. (Reproduced, with permission, from Peters et al. 1991.)

B. Regions on both sides of a node of Ranvier are rich in stable contacts between myelinating cells and the axon, to ensure that the nodes do not move or change in size and to restrict the localization of K⁺ and Na⁺ channels in the axon. Potassium permeable channels and the adhesion protein Caspr2 are concentrated in the juxtaparanode. Paranodal loops (PNL) of Schwann cell or oligodendrocyte cytoplasm form a series of stable junctions with the axon. The paranode region is rich with adhesion proteins such as Caspr2, contactin, and neurofascin (NF155). At the nodes in central axons, perinodal astroglial processes (PNP) contact the axonal membrane, which is enormously rich with Na⁺ channels. This localization of Na⁺ permeability is a major basis for the saltatory conduction in myelinated axons. The membrane-cytoskeletal linker ankyrin G (ankG) and the cell adhesion molecules NrCAM and NF186 are also concentrated at the nodes. (Reproduced, with permission, from Peles and Salzer 2000.)

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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.

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, P_0,, 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.

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.

Figures 4–15

A genetic disorder of myelination in mice can be partially cured by transfection of the normal gene that encodes myelin basic protein.

A. Electron micrographs show the state of myelination in the optic nerve of a normal mouse, a shiverer mutant, and a mutant transfected with the gene for myelin basic protein.

B. The shiverer mutant exhibits poor posture and weakness. Injection of the wild-type gene into the fertilized egg of the mutant improves myelination; the treated mutant looks as perky as a normal mouse. (Reproduced, with permission, from Readhead et al. 1987.)

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Figure 4–16

Charcot-Marie-Tooth disease (type 1A) results from increased production of peripheral myelin protein 22.

A. A patient with Charcot-Marie-Tooth disease shows impaired gait and deformities. (Reproduced, with permission, from Charcot's original description of the disease, Charcot and Marie 1886.)

B. The disordered myelination in Charcot-Marie-Tooth disease (type 1A) results from increased production of peripheral myelin protein 22 (PMP22).

1. Sural nerve biopsies from a normal individual (Reproduced, with permission, from A. P. Hays) and from a patient with Charcot-Marie-Tooth disease. (Reproduced, with permission, from Lupski and Garcia 1992.) In the patient's biopsy the myelin sheath is slightly thinner than normal and is surrounded by concentric rings of Schwann cell processes. These changes are typical of the recurrent demyelination and remyelination seen in this disorder.

2. The increase in PMP22 is caused by a duplication of a normal 1.5 megabase region of the DNA on the short arm of chromosome 17 at 17p11.2-p12. The PMP22 gene is flanked by two similar repeat sequences (CMT1A-REP), as shown in the normal chromosome 17 on the left. Normal individuals have two normal chromosomes. In patients with the disease (right) the duplication results in two functioning PMP22 genes, each flanked by a repeat sequence. The normal and duplicated regions are shown in the expanded diagrams indicated by the dashed lines. (The repeats are thought to have given rise to the original duplication, which was then inherited. The presence of two similar flanking sequences with homology to a transposable element is believed to increase the frequency of unequal crossing-over in this region of chromosome 17 because the repeats enhance the probability of mispairing of the two parental chromosomes in a fertilized egg.)

3. Although a large duplication (3 megabases) cannot be detected in routine examination of chromosomes in the light microscope, evidence for the duplication can be obtained using fluorescence in situ hybridization. The PMP22 gene is detected with an oligonucleotide probe tagged with the dye Texas Red. An oligonucleotide probe that hybridizes with DNA from region 11.2 (indicated by the green segment close to the centromere), is used for in situ hybridization on the same sample. A nucleus from a normal individual (left) shows a pair of chromosomes, each with one red site (PMP22 gene) for each green site. A nucleus from a patient with the disease (right) has one extra red site, indicating that one chromosome has one PMP22 gene and the other has two PMP22 genes. (Adapted, with permission, from Garcia et al. 1991.)

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Astrocytes Support Synaptic Signaling

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.

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).

Figure 4–17

Astrocyte processes are intimately associated with synapses.

A. Each of four adjacent astrocytes appears to occupy a distinct volume, with only a small overlap at the ends of their processes. In this overlap area astrocytes are connected to each other by gap junctions. Bar = 20 μm. (Reproduced, with permission, from Bushong et al. 2002.)

B. This high-voltage electron micrograph shows several thick processes emanating from the cell body of an astrocyte and branching into extraordinarily fine processes. The typical astrocyte envelopment of a blood vessel is shown at lower right. (Reproduced, with permission, from Hama, Ari, and Kosaka 1994.)

C. The processes of astrocytes are intimately associated with both presynaptic and postsynaptic elements. 1. The close association between astrocyte processes and synapses is seen in this electron micrograph of hippocampal cells. (Reproduced, with permission, from Ventura and Harris 1999.) 2. Glutamate released from the presynaptic neuron activates not only receptors on the postsynaptic neuron but also α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors on astrocytes. Astrocytes remove glutamate from the synaptic cleft by uptake through high-affinity transporters. (Reproduced, with permission, from Gallo and Chittajallu 2001.)

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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.

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.

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.

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.

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.

Choroid Plexus and Ependymal Cells Produce Cerebrospinal Fluid

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.

Figure 4–18

Ependyma and choroid plexus.

A. The ependyma is a single layer of ciliated, cuboidal cells lining the cerebral ventricles (V). High magnification of the ependymal lining (rectangle in upper image) shows the cilia on the ventricular side of the ependymal cells.

B. The choroid plexus is continuous with the ependyma but projects into the ventricles, where it covers thin blood vessels and forms a highly-branched, papillary structure. This is the site of cerebrospinal fluid formation. High magnification shows the blood vessel core (BV) and overlying choroid plexus (CP). The arrow denotes the direction of fluid flow from capillary into ventricle during the formation of cerebro spinal fluid.

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Microglia in the Brain Are Derived from Bone Marrow

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.

Figure 4–19

Large numbers of microglia reside in the mammalian central nervous system.

The micrograph on the left shows microglia in the cerebral cortex of an adult mouse (in brown, immunocytochemistry). The blue spots are the nuclei of nonmicroglial cells. The microglial cells have fine, lacy processes, as shown in the higher magnification micrograph on the right. (Reproduced, with permission, from Berry et al. 2002.)

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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.

An Overall View

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The morphology of neurons is elegantly suited to receive, conduct, and transmit signals. Dendrites provide a highly branched, elongated surface for receiving signals. Axons conduct electrical impulses rapidly over long distances to their synaptic terminals, which release neurotransmitters onto target cells. Although all neurons conform to the same basic cell plan, different types of neurons vary widely in their specific morphological features.

Neurons in different locations differ in the complexity of their dendritic trees, extent of axon branching, as well as in the number of synaptic terminals that they form and receive. The functional significance of these morphological differences is plainly evident. For example, motor neurons must have a more complex dendritic tree than sensory neurons, as even simple reflex activity requires integration of many excitatory and inhibitory inputs. As we shall see in subsequent chapters, different types of neurons have different neurotransmitters, ion channels, and neurotransmitter receptors. Together, these biochemical, morphological, and electrophysio logical differences contribute to the great complexity of information processing in the brain.

Most neuronal proteins are synthesized in the cell body, but some synthesis occurs in dendrites and axons. The newly synthesized proteins are folded with the assistance of chaperones, and their final structure is often modified by permanent or reversible post-translational modifications. The final destination of a protein in the neuron depends on signals encoded in its amino acid sequence. Transport of proteins and RNA occurs with great specificity and results in the vectorial transport of selected membrane components. The cytoskeleton provides an important framework for the transport of organelles to different intracellular locations in addition to controlling neuronal shape.

As we shall see in later chapters, all these fundamental cell-biological processes are profoundly controlled by electrical activity, which produces the dramatic changes in cell structure and function by which neural circuits adapt to experience (learning).

Finally, the nervous system also contains several types of glial cells. Oligodendrocytes and Schwann cells produce the myelin insulation that enables axons to conduct electrical signals rapidly. Astrocytes ensheath other parts of the neuron, particularly synapses. Glia control extracellular ion and neurotransmitter concentrations, and actively participate in the formation and function of synapses.

James H. Schwartz
Ben A. Barres
James E. Goldman

Selected Readings

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Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P, eds. 2002. Molecular Biology of the Cell, 4th ed. New York: Garland.

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Figure 4–1

The structure of a neuron.

Figure 4–2

Organelles of the neuron.

Figure 4–3

Golgi and endoplasmic reticulum membranes extend from the cell body into dendrites.

Figure 4–4

Types of dendritic spines.

Figure 4–5

Atlas of fibrillary structures.

Figure 4–6

Abnormal aggregates of proteins inside neurons in Alzheimer and Parkinson diseases.

Figure 4–7

The cytoskeletal structure of an axon.

Figure 4–8

Membrane trafficking in the neuron.

Figure 4–9

Axonal transport of the herpes simplex virus (HSV) is used to trace cortical pathways in monkeys.

Fast Axonal Transport Carries Membranous Organelles

Figure 4–10

Early experiments on anterograde axonal transport used radioactive labeling of proteins.

Figure 4–11

Ribosomes in the dendritic arbor.

Slow Axonal Transport Carries Cytosolic Proteins and Elements of the Cytoskeleton

Secretory and Membrane Proteins Are Synthesized and Modified in the Endoplasmic Reticulum

Figure 4–12

Protein synthesis in the endoplasmic reticulum.

Secretory Proteins Are Modified in the Golgi Complex

Glia Form the Insulating Sheaths for Axons

Figure 4–13

Myelin insulates the axons of both central and peripheral neurons.

Figure 4–14

The myelin sheath of axons has regular gaps called the nodes of Ranvier.

Figures 4–15

A genetic disorder of myelination in mice can be partially cured by transfection of the normal gene that encodes myelin basic protein.

Figure 4–16

Charcot-Marie-Tooth disease (type 1A) results from increased production of peripheral myelin protein 22.

Astrocytes Support Synaptic Signaling

Figure 4–17

Astrocyte processes are intimately associated with synapses.

Choroid Plexus and Ependymal Cells Produce Cerebrospinal Fluid

Figure 4–18

Ependyma and choroid plexus.

Microglia in the Brain Are Derived from Bone Marrow

Figure 4–19

Large numbers of microglia reside in the mammalian central nervous system.

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