Nissl Substance

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It is interesting that Nissl recognized the composite nature of the substance named for him, although he could not have resolved either of its components.

The preceding quote and the following discussion of the Nissl substance appeared in L. Sanford, M. D. Palay, and G. E. Palade (1955). The fine structure of neurons. J. Biophys. Biochem. Cytol. 88, 69-88.

As imaged in the electron microscope, the crowded cytoplasm of the neuron contrasts sharply with the relatively open cytoplasm of many other cell types. As this compact appearance stems largely from the extensive meshwork of Nissl substance, the neuron resembles, even at the electron microscope level, certain protein-secreting glandular cells, such as those of the pancreatic acini and the salivary glands .. .

Like the basophilic substance or ergasto-plasm of glandular cells, the Nissl substance is a composite material constructed of endoplasmic reticulum and fine granules, both of which have been revealed by electron microscopy. The first component of the Nissl substance appears to be part of the general endoplasmic reticulum of the neuron. The reticulum extends throughout the entire cytoplasm, but is considerably more condensed within the area of the Nissl bodies than in the rest of the cell. These condensations not only determine the size and shape of each Nissl body, but also constitute a membranous framework upon which the other components are arranged. In many types of neurons, the meshes of the endoplasmic reticulum are distributed at random in three dimensions but in all neurons, and especially in the large motor neurons, the endoplasmic reticulum may display a distinctly orderly arrangement within the Nissl bodies. This orientation consists of a layering of reticu-

lar sheets, at more or less regular intervals. Each sheet is a reticulum developed predominantly in two dimensions and comprising tubules, strings of vesicles, and numerous large and flat cister-nae. Even in such highly ordered forms as the Nissl bodies of motor neurons, the continuity of the reticulum persists, as indicated by frequent branches and anastomoses between layers.

The second component of the Nissl substance is represented by small granules disposed in patterned arrays either in close contact with the outer membranes of the endo-plasmic reticulum or scattered in the intervening matrix. This matrix may be considered as a third component of the Nissl substance. It is evident, therefore, that although the Nissl bodies are differentiated parts of the cytoplasm, they are continuous with it by virtue of the continuity of the endoplasmic reticulum and the matrix. No interface or membrane separates them from the rest of the cytoplasm. In this respect, as well as in general architecture, they are comparable to the ergastoplasm of glandular cells. The only differences lie in (a) a different intracellular distribution, (b) a lesser degree of preferred orientation of the endo-plasmic reticulum, and (c) an apparently greater concentration of fine granules within the areas of the Nissl bodies.

We now recognize that the electron-dense "granules" are ribosomes, arranged in cytoplasmic "free" polysomal rosettes (see box in Fig. 2.1), or attached to the surface of the endoplasmic reticulum membrane. The lumen of the ER compartment (arrow) contains a "fuzz" that probably is formed by the numerous nascent chains being cotrans-lationally inserted into the ER lumen, some resident proteins that take part in the translation process, and certain structural components of the ER membrane.

(Box 2.1, Fig. 2.1). This arrangement is unique to neurons, and its functional significance is unknown. Most, but by no means all, proteins used throughout the neuron are synthesized in the perikaryon. During or after synthesis and processing, proteins are packaged into membrane-limited organelles, are incorpo-

rated into cytoskeletal elements, or remain as soluble constituents of the cytoplasm. After proteins have been packaged appropriately, they are transported to their sites of function.

With a few exceptions, vertebrate neurons have two discrete functional domains or compartments, the

Neuron Nissl Substance

FIGURE 2.1 The "Nissl body" in neurons is an array of cytoplasmic free polysomal rosettes (boxed) interspersed between rows of rough endoplasmic reticulum (RER) studded with membrane-bound ribosomes. Nascent polypeptide chains emerging from the ribosomal tunnel on the RER are inserted into the lumen (arrow), where they may be processed before transport out of the RER. The relationship between the polypeptide products of these "free" and "bound" polysome populations in the Nissl body, an arrangement that is unique to neurons, is unknown.

FIGURE 2.1 The "Nissl body" in neurons is an array of cytoplasmic free polysomal rosettes (boxed) interspersed between rows of rough endoplasmic reticulum (RER) studded with membrane-bound ribosomes. Nascent polypeptide chains emerging from the ribosomal tunnel on the RER are inserted into the lumen (arrow), where they may be processed before transport out of the RER. The relationship between the polypeptide products of these "free" and "bound" polysome populations in the Nissl body, an arrangement that is unique to neurons, is unknown.

axonal and the somatodendritic compartments, each of which encompasses a number of sub- or microdomains (Fig. 2.2). The axon is perhaps the most familiar functional domain of a neuron (Lasek and Brady, 1982) and is classically defined as the cellular process by which a neuron makes contact with a target cell to transmit information, providing a conducting structure for transmitting the action potential to a synapse, a specialized subdomain for transmission of a signal from neuron to target cell (neuron, muscle, etc.), most often by release of appropriate neurotrans-mitters. Consequently, most axons end in a presynap-tic terminal, although a single axon may have many (hundreds or even thousands in some cases) presynap-tic specializations known as en passant synapses along its length. Characteristics of presynaptic terminals are presented in greater detail later in this chapter.

The axon is the first neuronal process to differentiate during development. A typical neuron has only a single axon that proceeds some distance from the cell body before branching extensively. Usually the longest process of a neuron, axons come in many sizes. In a human adult, axons range in length from a few micrometers for small interneurons to a meter or more for large motor neurons, and they may be even longer in large animals (such as giraffes, elephants, and whales). In mammals and other vertebrates, the longest axons generally extend approximately half the body length.

Axonal diameters also are quite variable, ranging from 0.1 to 20 ^m for large myelinated fibers in vertebrates. Invertebrate axons grow to even larger diameters, with the giant axons of some squid species achieving diameters in the millimeter range (see Fig. 5.1A). Invertebrate axons reach such large diameters because they lack the myelinating glia that speed conduction of the action potential. As a result, axonal caliber must be large to sustain the high rate of conduction needed for the reflexes that permit escape from predators and capture of prey. Although axonal caliber is closely regulated in both myelinated and nonmyelinated fibers, this parameter is critical for those organisms that are unable to produce myelin.

The region of the neuronal cell body where the axon originates has several specialized features. This domain, called the axon hillock, is most readily distinguished by a deficiency of Nissl substance. Therefore, protein synthesis cannot take place to any appreciable degree in this region. Cytoplasm in the vicinity of the axon hillock may have a few polysomes but is dominated by the cytoskeletal and membranous organelles that are being delivered to the axon. Microtubules and neurofilaments begin to align roughly parallel to each other, helping to organize membrane-limited organelles destined for the axon. The hillock is a region where materials either are committed to the axon (cytoskeletal elements, synaptic vesicle precursors, mitochondria, etc.) or are excluded from the axon (RER and free polysomes, dendritic microtubule-associated proteins). The molecular basis for this sorting is not understood. Cytoplasm in the axon hillock does not appear to contain a physical "sizing" barrier (like a filter) because large organelles such as mitochondria readily enter the axon, whereas only a small number of essentially excluded structures such as polysomes are occasionally seen only in the initial segment of the axon and not in the axon proper. An exception to this general rule is during development when local protein synthesis does take place at the axon terminus or growth cone. In the mature neuron, the physiological significance of this barrier must be considerable, because axonal structures are found to accumulate in this region in many neuropathologies, including those due to degenerative diseases (such as amyotrophic lateral sclerosis) and to exposure to neurotoxic compounds (such as acrylamide).

The initial segment of the axon is the region of the axon adjacent to the axon hillock. Microtubules gener-

Axon Hillock MicrotubulesNeurone Nissl

FIGURE 2.2 Basic elements of neuronal subcellular organization. The neuron consists of a soma, or cell body, in which the nucleus, multiple cytoplasm-filled processes termed dendrites, and the (usually single) axon are located. The neuron is highly extended in space; a neuron with a cell body of the size shown here could easily maintain an axon several miles in length! The unique shape of each neuron is the result of a cooperative interplay between plasma membrane components (the lipid matrix and associated proteins) and cytoskeletal elements. Most large neurons in vertebrates are myelinated by oligodendrocytes in the CNS and Schwann cells in the PNS. The compact wraps of myelin encasing the axon distal to the initial segment permit the rapid conduction of the action potential by a process termed "saltatory conduction" (see Chapters 1, 4, and 5).

FIGURE 2.2 Basic elements of neuronal subcellular organization. The neuron consists of a soma, or cell body, in which the nucleus, multiple cytoplasm-filled processes termed dendrites, and the (usually single) axon are located. The neuron is highly extended in space; a neuron with a cell body of the size shown here could easily maintain an axon several miles in length! The unique shape of each neuron is the result of a cooperative interplay between plasma membrane components (the lipid matrix and associated proteins) and cytoskeletal elements. Most large neurons in vertebrates are myelinated by oligodendrocytes in the CNS and Schwann cells in the PNS. The compact wraps of myelin encasing the axon distal to the initial segment permit the rapid conduction of the action potential by a process termed "saltatory conduction" (see Chapters 1, 4, and 5).

ally form characteristic fascicles, or bundles, in the initial segment of the axon. These fascicles are not seen elsewhere. The initial segment and, to some extent, the axon hillock also have a distinctive specialized plasma membrane. Initially, the plasmalemma was thought to have a thick electron-dense coating actually attached to the inner surface of the membrane, but this dense undercoating is in reality separated by 5 to 10 nm from the plasma membrane inner surface and has a complex ultrastructure. Neither the composition nor the function of this undercoating is known. Curiously, the undercoating is present in the same regions of the initial segment as the distinctive fasciculation of microtubules, although the relationship is not understood. The plasma membrane is specialized in the initial segment and axon hillock in that it contains voltage-sensitive ion channels in large numbers, and most action potentials originate in this domain.

Ultimately, axonal structure is geared toward the efficient conduction of action potentials at a rate appropriate to the function of that neuron. This can be seen from both the ultrastructure and the composition of axons. Axons are roughly cylindrical in cross section with little or no taper. As discussed later in this chapter, this diameter is maintained by regulation of the cytoskeleton. Even at branch points, daughter axons are comparable in diameter to the parent axon. This constant caliber helps ensure a consistent rate of conduction. Similarly, the organization of membrane components is regulated to this end. Voltage-gated ion channels are distributed to maximize conduction. Sodium channels are distributed more or less uniformly in small nonmyelinated axons, but are concentrated at high density in the regularly spaced unmyelinated gaps, known as nodes of Ranvier (see Figs. 1.14, 2.2, and 5.8). An axon so organized will conduct an action potential or train of spikes long distances with high fidelity at a defined speed. These characteristics are essential for maintaining the precise timing and coordination seen in neuronal circuits.

Most vertebrate neurons have multiple dendrites arising from their perikarya. Unlike axons, dendrites continuously branch and taper extensively, with a reduction in caliber in daughter processes at each branching. In addition, the surface of dendrites is covered with small protrusions, or spines, which are postsynaptic specializations (see also Chapters 1, 4, 17, and 18). Although the surface area of a dendritic arbor may be quite extensive, dendrites in general remain in the relative vicinity of the perikaryon. A dendritic arbor may be contacted by the axons of many different and distant neurons or innervated by a single axon making multiple synaptic contacts.

The base of a dendrite is continuous with the cytoplasm of the cell body. In contrast to the axon, Nissl substance extends into dendrites, and certain proteins are synthesized predominantly in dendrites. There is evidence for the selective placement of some mRNAs in dendrites as well (Steward, 1995). For example, whereas RER and polysomes extend well into the dendrites, the mRNAs that are transported and translated in dendrites are a subset of the total neuronal mRNA, deficient in some mRNA species (such as neurofilament mRNAs) and enriched in mRNAs with dendritic functions (such as microtubule-associated protein mRNAs, microtubule-associated protein 2). Also, certain proteins appear to be targeted, postsyn-thesis, to the dendritic compartment as well.

The shapes and complexity of dendritic arborizations may be remarkably plastic. Dendrites appear relatively late in development and initially have only limited numbers of branches and spines. As development and maturation of the nervous system proceed, the size and number of branches increase. The number of spines increases dramatically, and their distribution may change. This remodeling of synaptic connectivity may continue into adulthood, and environmental effects can alter this pattern significantly. Eventually, in the aging brain, there is a reduction in complexity and size of dendritic arbors, with fewer spines and thinner dendritic shafts. These changes correlate with changes in neuronal function during development and aging.

As defined by classic physiology, axons are the structural correlates for neuronal output, and den-drites constitute the domain for receiving information. A neuron without an axon or one without dendrites might therefore seem paradoxical, but such neurons do exist. Certain amacrine and horizontal cells in the vertebrate retina have no identifiable axons, although they do have dendritic processes that are morphologically distinct from axons. Such processes may have both pre- and postsynaptic specializations or they may have gap junctions (Chapter 15) that act as direct electrical connections between two cells. Similarly, the pseudounipolar sensory neurons of dorsal root ganglia (DRG) have no dendrites. In their mature form, these DRG sensory neurons give rise to a single axon that extends a few hundred micrometers before branching. One long branch extends to the periphery, where it may form a sensory nerve ending in muscle spindles or skin. Large DRG peripheral branches are myelinated and have the morphological characteristics of an axon, but they contain neither pre- nor postsynaptic specializations. The other branch extends into the central nervous system, where it forms synaptic contacts. In

2. SUBCELLULAR ORGANIZATION OF THE NERVOUS SYSTEM TABLE 2.1 Functional and Morphological Hallmarks of Axons and Dendrites3

Axons

With rare exceptions, each neuron has a single axon.

Axons appear first during neuronal differentiation.

Axon initial segments are distinguished by a specialized plasma membrane containing a high density of ion channels and distinctive cytoskeletal organization.

Axons typically are cylindrical in form with a round or elliptical cross section.

Large axons are myelinated in vertebrates, and the thickness of the myelin sheath is proportional to the axonal caliber.

Axon caliber is a function of neurofilament and microtubule numbers, with neurofilaments predominating in large axons.

Microtubules in axons have a uniform polarity with plus ends distal from the cell body.

Axonal microtubules are enriched in tau protein with a characteristic phosphorylation pattern.

Ribosomes are excluded from mature axons, although a few may be detectable in initial segments.

Axonal branches tend to be distal from the cell body.

Axonal branches form obtuse angles and have diameters similar to the parent stem.

Most axons have presynaptic specializations that may be en passant or at the ends of axonal branches.

Action potentials are usually generated at the axon hillock and conducted away from the cell body.

Traditionally, axons are specialized for conduction and synaptic transmission, i.e., neuronal output.

Dendrites

Most neurons have multiple dendrites arising from their cell bodies.

Dendrites begin to differentiate only after the axon has formed.

Dendrites are continuous with the perikaryal cytoplasm, and the transition point cannot be readily distinguished.

Dendrites usually have a significant taper and small spinous processes that give them an irregular cross section.

Dendrites are not myelinated, although a few wraps of myelin may occur rarely.

The dendritic cytoskeleton may appear less organized, and microtubules dominate even in large dendrites.

Microtubules in proximal dendrites have mixed polarity, with both plus and minus ends oriented distal to the cell body.

Dendritic microtubules may contain some tau protein, but MAP2 is not present in axonal compartments and is highly enriched in dendrites.

Both rough endoplasmic reticulum and cytoplasmic polysomes are present in dendrites, with specific mRNAs being enriched in dendrites.

Dendrites begin to branch extensively near the perikaryon and form extensive arbors in the vicinity of the perikaryon.

Dendritic branches form acute angles and are smaller than the parent stem.

Dendrites are rich in postsynaptic specializations, particularly on the spinous processes that project from the dendritic shaft.

Some dendrites can generate action potentials, but more commonly they modulate the electrical state of the perikaryon and initial segment.

Dendritic architecture is most suitable for integrating synaptic responses from a variety of inputs, i.e., neuronal input.

a Neurons typically have two classes of cytoplasmic extensions that may be distinguished using electrophysiological, morphological, and biochemical criteria. Although some neuronal processes may lack one or more of these features, enough parameters can generally be defined to allow unambiguous identification.

DRG neurons, the action potential is generated at distal sensory nerve endings and then transmitted along the peripheral branch to the central branch and the appropriate CNS targets, bypassing the cell body. The functional and morphological hallmarks of axons and dendrites are listed in Table 2.1.

Summary

Neurons are polarized cells that are specialized for membrane and protein synthesis as well as for conduction of the nerve impulse. In general, neurons have a cell body, a dendritic arborization that is usually located near the cell body, and an extended axon that may branch considerably before terminating to form synapses with other neurons.

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  • Rhiannon
    Where is the nissl substance of a neuron?
    2 years ago

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